|
1
|
Adams RC, MacDonald KPA, Hill GR. The contribution of the monocyte-macrophage lineage to immunotherapy outcomes. Blood 2025; 145:1010-1021. [PMID: 39576958 DOI: 10.1182/blood.2024025680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 10/21/2024] [Accepted: 11/04/2024] [Indexed: 11/24/2024] Open
Abstract
ABSTRACT Macrophages execute core functions in maintaining tissue homeostasis, in which their extensive plasticity permits a spectrum of functions from tissue remodeling to immune defense. However, perturbations to tissue-resident macrophages during disease, and the subsequent emergence of monocyte-derived macrophages, can hinder tissue recovery and promote further damage through inflammatory and fibrotic programs. Gaining a fundamental understanding of the critical pathways defining pathogenic macrophage populations enables the development of targeted therapeutic approaches to improve disease outcomes. In the setting of chronic graft-versus-host disease (cGVHD), which remains the major complication of allogeneic hematopoietic stem cell transplantation, colony-stimulating factor 1 (CSF1)-dependent donor-derived macrophages have been identified as key pathogenic mediators of fibrotic skin and lung disease. Antibody blockade of the CSF1 receptor (CSF1R) to induce macrophage depletion showed remarkable capacity to prevent fibrosis in preclinical models and has subsequently demonstrated impressive efficacy for improving cGVHD in ongoing clinical trials. Similarly, macrophage depletion approaches are currently under investigation for their potential to augment responses to immune checkpoint inhibition. Moreover, both monocyte and tissue-resident macrophage populations have recently been implicated as mediators of the numerous toxicities associated with chimeric antigen receptor T-cell therapy, further highlighting potential avenues of macrophage-based interventions to improve clinical outcomes. Herein, we examine the current literature on basic macrophage biology and contextualize this in the setting of cellular and immunotherapy. Additionally, we highlight mechanisms by which macrophages can be targeted, largely by interfering with the CSF1/CSF1R signaling axis, for therapeutic benefit in the context of both cellular and immunotherapy.
Collapse
Affiliation(s)
- Rachael C Adams
- Infection and Inflammation Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA
| | - Kelli P A MacDonald
- Infection and Inflammation Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Geoffrey R Hill
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA
| |
Collapse
|
|
2
|
Rayasam A, Moe A, Kudek M, Shah RK, Yuan CY, Miller JM, Rau M, Patton M, Wanat K, Colonna M, Zamora AE, Drobyski WR. Intestinal epithelium-derived IL-34 reprograms macrophages to mitigate gastrointestinal tract graft-versus-host disease. Sci Transl Med 2025; 17:eadn3963. [PMID: 39937882 DOI: 10.1126/scitranslmed.adn3963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 10/10/2024] [Accepted: 01/08/2025] [Indexed: 02/14/2025]
Abstract
Gastrointestinal (GI) tract graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation and is attributable to dysregulation that occurs between the effector and regulatory arms of the immune system. Whereas regulatory T cells have a primary role in counterbalancing GVHD-induced inflammation, identifying and harnessing other pathways that promote immune tolerance remain major goals in this disease. Herein, we identified interleukin-34 (IL-34) as an intestinal epithelium-derived cytokine that was able to mitigate the severity of GVHD within the GI tract. Specifically, we observed that the absence of recipient IL-34 production exacerbated GVHD lethality, promoted intestinal epithelial cell death, and compromised barrier integrity. Mechanistically, the absence of host IL-34 skewed donor macrophages toward a proinflammatory phenotype and augmented the accumulation of pathogenic CD4+ granulocyte-macrophage colony-stimulating factor (GM-CSF)+ T cells within the colon. Conversely, the administration of recombinant IL-34 substantially reduced GVHD mortality and inflammation, which was dependent on the expression of apolipoprotein E in donor macrophages. Complementary genetic and imaging approaches in mice demonstrated that intestinal epithelial cells were the relevant source of IL-34. These results were supported by colonic biopsies from patients with GVHD, which displayed IL-34 expression in intestinal epithelial cells and apolipoprotein E in lamina propria macrophages, validating similar cellular localization in humans. These studies indicate that IL-34 acts as a tissue-intrinsic cytokine that regulates GVHD severity in the GI tract and could serve as a potential therapeutic target for amelioration of this disease.
Collapse
Affiliation(s)
- Aditya Rayasam
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Alison Moe
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Matthew Kudek
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Ravi K Shah
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Cheng-Yin Yuan
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - James M Miller
- Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Mary Rau
- Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Mollie Patton
- Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Karolyn Wanat
- Department of Dermatology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Marco Colonna
- Department of Pathology and Immunology, Washington University, Saint Louis, MO 63110, USA
| | - Anthony E Zamora
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - William R Drobyski
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| |
Collapse
|
|
3
|
Mohamed SH, Vanhoffelen E, Shun Fu M, Hei Lau P, Hain S, Seldeslachts L, Cosway E, Anderson G, McCulloch L, Vande Velde G, Drummond RA. CSF1R inhibition by PLX5622 reduces pulmonary fungal infection by depleting MHCII hi interstitial lung macrophages. Mucosal Immunol 2024; 17:1256-1272. [PMID: 39168451 DOI: 10.1016/j.mucimm.2024.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 08/08/2024] [Accepted: 08/14/2024] [Indexed: 08/23/2024]
Abstract
PLX5622 is a small molecular inhibitor of the CSF1 receptor (CSF1R) and is widely used to deplete macrophages within the central nervous system (CNS). We investigated the impact of PLX5622 treatment in wild-type C57BL/6 mice and discovered that one-week treatment with PLX5622 was sufficient to deplete interstitial macrophages in the lung and brain-infiltrating Ly6Clow patrolling monocytes, in addition to CNS-resident macrophages. These cell types were previously indicated to act as infection reservoirs for the pathogenic fungus Cryptococcus neoformans. We found that PLX5622-treated mice had significantly reduced fungal lung infection and reduced extrapulmonary dissemination to the CNS but not to the spleen or liver. Fungal lung infection mapped to MHCIIhi interstitial lung macrophages, which underwent significant expansion during infection following monocyte replenishment and not local division. Although PLX5622 depleted CNS infiltrating patrolling monocytes, these cells did not accumulate in the fungal-infected CNS following pulmonary infection. In addition, Nr4a1-deficient mice, which lack patrolling monocytes, had similar control and dissemination of C. neoformans infection to wild-type controls. PLX5622 did not directly affect CD4 T-cell responses, or significantly affect production of antibody in the lung during infection. However, we found that mice lacking lymphocytes had reduced numbers of MHCIIhi interstitial macrophages in the lung, which correlated with reduced infection load. Accordingly, PLX5622 treatment did not alter fungal burdens in the lungs of lymphocyte-deficient mice. Our data demonstrate that PLX5622 may help reduce lung burden of pathogenic fungi that utilise CSF1R-dependent myeloid cells as infection reservoirs, an effect which is dependent on the presence of lymphocytes.
Collapse
Affiliation(s)
- Sally H Mohamed
- Institute of Immunology & Immunotherapy, University of Birmingham, UK
| | - Eliane Vanhoffelen
- Department of Imaging and Pathology, Biomedical MRI/MoSAIC, KU Leuven, Leuven, Belgium
| | - Man Shun Fu
- Institute of Immunology & Immunotherapy, University of Birmingham, UK
| | - Pui Hei Lau
- Institute of Immunology & Immunotherapy, University of Birmingham, UK
| | - Sofia Hain
- Institute of Immunology & Immunotherapy, University of Birmingham, UK
| | - Laura Seldeslachts
- Department of Imaging and Pathology, Biomedical MRI/MoSAIC, KU Leuven, Leuven, Belgium
| | - Emilie Cosway
- Institute of Immunology & Immunotherapy, University of Birmingham, UK
| | - Graham Anderson
- Institute of Immunology & Immunotherapy, University of Birmingham, UK
| | - Laura McCulloch
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Greetje Vande Velde
- Department of Imaging and Pathology, Biomedical MRI/MoSAIC, KU Leuven, Leuven, Belgium
| | - Rebecca A Drummond
- Institute of Immunology & Immunotherapy, University of Birmingham, UK; Institute of Microbiology & Infection, University of Birmingham, UK.
| |
Collapse
|
|
4
|
Xinyi Y, Vladimirovich RI, Beeraka NM, Satyavathi A, Kamble D, Nikolenko VN, Lakshmi AN, Basappa B, Reddy Y P, Fan R, Liu J. Emerging insights into epigenetics and hematopoietic stem cell trafficking in age-related hematological malignancies. Stem Cell Res Ther 2024; 15:401. [PMID: 39506818 PMCID: PMC11539620 DOI: 10.1186/s13287-024-04008-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 10/22/2024] [Indexed: 11/08/2024] Open
Abstract
BACKGROUND Hematopoiesis within the bone marrow (BM) is a complex and tightly regulated process predominantly influenced by immune factors. Aging, diabetes, and obesity are significant contributors to BM niche damage, which can alter hematopoiesis and lead to the development of clonal hematopoiesis of intermediate potential (CHIP). Genetic/epigenetic alterations during aging could influence BM niche reorganization for hematopoiesis or clonal hematopoiesis. CHIP is driven by mutations in genes such as Tet2, Dnmt3a, Asxl1, and Jak2, which are associated with age-related hematological malignancies. OBJECTIVE This literature review aims to provide an updated exploration of the functional aspects of BM niche cells within the hematopoietic microenvironment in the context of age-related hematological malignancies. The review specifically focuses on how immunological stressors modulate different signaling pathways that impact hematopoiesis. METHODS An extensive review of recent studies was conducted, examining the roles of various BM niche cells in hematopoietic stem cell (HSC) trafficking and the development of age-related hematological malignancies. Emphasis was placed on understanding the influence of immunological stressors on these processes. RESULTS Recent findings reveal a significant microheterogeneity and temporal stochasticity of niche cells across the BM during hematopoiesis. These studies demonstrate that niche cells, including mesenchymal stem cells, osteoblasts, and endothelial cells, exhibit dynamic interactions with HSCs, significantly influenced by the BM microenvironment as the age increases. Immunosurveillance plays a crucial role in maintaining hematopoietic homeostasis, with alterations in immune signaling pathways contributing to the onset of hematological malignancies. Novel insights into the interaction between niche cells and HSCs under stress/aging conditions highlight the importance of niche plasticity and adaptability. CONCLUSION The involvement of age-induced genetic/epigenetic alterations in BM niche cells and immunological stressors in hematopoiesis is crucial for understanding the development of age-related hematological malignancies. This comprehensive review provides new insights into the complex interplay between niche cells and HSCs, emphasizing the potential for novel therapeutic approaches that target niche cell functionality and resilience to improve hematopoietic outcomes in the context of aging and metabolic disorders. NOVELTY STATEMENT This review introduces novel concepts regarding the plasticity and adaptability of BM niche cells in response to immunological stressors and epigenetics. It proposes that targeted therapeutic strategies aimed at enhancing niche cell resilience could mitigate the adverse effects of aging, diabetes, and obesity on hematopoiesis and clonal hematopoiesis. Additionally, the review suggests that understanding the precise temporal and spatial dynamics of niche-HSC interactions and epigenetics influence may lead to innovative treatments for age-related hematological malignancies.
Collapse
Affiliation(s)
- Yang Xinyi
- Department of Oncology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Str, Moscow, 119991, Russia
| | - Reshetov Igor Vladimirovich
- Department of Oncology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Str, Moscow, 119991, Russia
| | - Narasimha M Beeraka
- Department of Human Anatomy and Histology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Str, Moscow, 119991, Russia.
- Raghavendra Institute of Pharmaceutical Education and Research (RIPER), Anantapuramu, Chiyyedu, Andhra Pradesh, 515721, India.
- Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, 1044 W. Walnut Street, R4-168, Indianapolis, IN, 46202, USA.
- Department of Studies in Molecular Biology, Faculty of Science and Technology, University of Mysore, Mysore, Karnataka, 570006, India.
| | - Allaka Satyavathi
- Department of Chemistry, Faculty of science, Dr B R Ambedkar Open University, Wanaparthy, Telangana, 509103, India
| | - Dinisha Kamble
- Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, 1044 W. Walnut Street, R4-168, Indianapolis, IN, 46202, USA
| | - Vladimir N Nikolenko
- Department of Human Anatomy and Histology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Str, Moscow, 119991, Russia
| | - Allaka Naga Lakshmi
- Department of Computer Science, St Philomena's College (Autonomous), Bangalore - Mysore Rd, Bannimantap, Mysuru, Karnataka, 570015, India
| | - Basappa Basappa
- Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Mysore, Karnataka, 570006, India
| | - Padmanabha Reddy Y
- Raghavendra Institute of Pharmaceutical Education and Research (RIPER), Anantapuramu, Chiyyedu, Andhra Pradesh, 515721, India
| | - Ruitai Fan
- Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450000, China.
| | - Junqi Liu
- Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450000, China
| |
Collapse
|
|
5
|
Wolff D, Cutler C, Lee SJ, Pusic I, Bittencourt H, White J, Hamadani M, Arai S, Salhotra A, Perez-Simon JA, Alousi A, Choe H, Kwon M, Bermúdez A, Kim I, Socié G, Chhabra S, Radojcic V, O'Toole T, Tian C, Ordentlich P, DeFilipp Z, Kitko CL. Axatilimab in Recurrent or Refractory Chronic Graft-versus-Host Disease. N Engl J Med 2024; 391:1002-1014. [PMID: 39292927 DOI: 10.1056/nejmoa2401537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/20/2024]
Abstract
BACKGROUND Colony-stimulating factor 1 receptor (CSF1R)-dependent monocytes and macrophages are key mediators of chronic graft-versus-host disease (GVHD), a major long-term complication of allogeneic hematopoietic stem-cell transplantation. The CSF1R-blocking antibody axatilimab has shown promising clinical activity in chronic GVHD. METHODS In this phase 2, multinational, pivotal, randomized study, we evaluated axatilimab at three different doses in patients with recurrent or refractory chronic GVHD. Patients were randomly assigned to receive axatilimab, administered intravenously, at a dose of 0.3 mg per kilogram of body weight every 2 weeks (0.3-mg dose group), at a dose of 1 mg per kilogram every 2 weeks (1-mg dose group), or at a dose of 3 mg per kilogram every 4 weeks (3-mg dose group). The primary end point was overall response (complete or partial response) in the first six cycles; the key secondary end point was a patient-reported decrease in chronic GVHD symptom burden, as assessed by a reduction of more than 5 points on the modified Lee Symptom Scale (range, 0 to 100, with higher scores indicating worse symptoms). The primary end point would be met if the lower bound of the 95% confidence interval exceeded 30%. RESULTS A total of 241 patients were enrolled (80 patients in the 0.3-mg dose group, 81 in the 1-mg dose group, and 80 in the 3-mg dose group). The primary end point was met in all the groups; an overall response was observed in 74% (95% confidence interval [CI], 63 to 83) of the patients in the 0.3-mg dose group, 67% (95% CI, 55 to 77) of the patients in the 1-mg dose group, and 50% (95% CI, 39 to 61) of the patients in the 3-mg dose group. A reduction of more than 5 points on the modified Lee Symptom Scale was reported in 60%, 69%, and 41% of the patients in the three dose groups, respectively. The most common adverse events were dose-dependent transient laboratory abnormalities related to CSF1R blockade. Adverse events leading to discontinuation of axatilimab occurred in 6% of the patients in the 0.3-mg dose group, 22% in the 1-mg dose group, and 18% in the 3-mg dose group. CONCLUSIONS Targeting CSF1R-dependent monocytes and macrophages with axatilimab resulted in a high incidence of response among patients with recurrent or refractory chronic GVHD. (Funded by Syndax Pharmaceuticals and Incyte; AGAVE-201 ClinicalTrials.gov number, NCT04710576.).
Collapse
Affiliation(s)
- Daniel Wolff
- From University Hospital Regensburg, Regensburg, Germany (D.W.); Dana-Farber Cancer Institute and Harvard Medical School (C.C.) and Massachusetts General Hospital (Z.D.), Boston, and Syndax Pharmaceuticals, Waltham (V.R., T.O., P.O.) - all in Massachusetts; Fred Hutchinson Cancer Center, Seattle (S.J.L.); Washington University School of Medicine, St. Louis (I.P.); Centre Hospitalier Universitaire Sainte-Justine, Montreal (H.B.), and the University of British Columbia, Vancouver General Hospital, Vancouver (J.W.) - both in Canada; the Medical College of Wisconsin, Milwaukee (M.H., S.C.); Stanford Health Care, Stanford (S.A.), and City of Hope Medical Center, Duarte (A.S.) - both in California; Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBiS), CSIC, Universidad de Sevilla, Seville (J.A.P.-S.), Hospital General Universitario Gregorio Marañón, Instituto de Investigación Biomédica Gregorio Marañón, and Universidad Complutense de Madrid, Madrid (M.K.), and Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, Santander (A.B.) - all in Spain; the M.D. Anderson Cancer Center, Houston (A.A.); the James Cancer Hospital and Solove Research Institute and Ohio State University Wexner Medical Center, Columbus (H.C.); Seoul National University College of Internal Medicine, Seoul, South Korea (I.K.); Hôpital Saint-Louis and University Paris Cité, Paris (G.S.); Incyte Corporation, Wilmington, DE (C.T.); and Vanderbilt University Medical Center, Nashville (C.L.K.)
| | - Corey Cutler
- From University Hospital Regensburg, Regensburg, Germany (D.W.); Dana-Farber Cancer Institute and Harvard Medical School (C.C.) and Massachusetts General Hospital (Z.D.), Boston, and Syndax Pharmaceuticals, Waltham (V.R., T.O., P.O.) - all in Massachusetts; Fred Hutchinson Cancer Center, Seattle (S.J.L.); Washington University School of Medicine, St. Louis (I.P.); Centre Hospitalier Universitaire Sainte-Justine, Montreal (H.B.), and the University of British Columbia, Vancouver General Hospital, Vancouver (J.W.) - both in Canada; the Medical College of Wisconsin, Milwaukee (M.H., S.C.); Stanford Health Care, Stanford (S.A.), and City of Hope Medical Center, Duarte (A.S.) - both in California; Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBiS), CSIC, Universidad de Sevilla, Seville (J.A.P.-S.), Hospital General Universitario Gregorio Marañón, Instituto de Investigación Biomédica Gregorio Marañón, and Universidad Complutense de Madrid, Madrid (M.K.), and Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, Santander (A.B.) - all in Spain; the M.D. Anderson Cancer Center, Houston (A.A.); the James Cancer Hospital and Solove Research Institute and Ohio State University Wexner Medical Center, Columbus (H.C.); Seoul National University College of Internal Medicine, Seoul, South Korea (I.K.); Hôpital Saint-Louis and University Paris Cité, Paris (G.S.); Incyte Corporation, Wilmington, DE (C.T.); and Vanderbilt University Medical Center, Nashville (C.L.K.)
| | - Stephanie J Lee
- From University Hospital Regensburg, Regensburg, Germany (D.W.); Dana-Farber Cancer Institute and Harvard Medical School (C.C.) and Massachusetts General Hospital (Z.D.), Boston, and Syndax Pharmaceuticals, Waltham (V.R., T.O., P.O.) - all in Massachusetts; Fred Hutchinson Cancer Center, Seattle (S.J.L.); Washington University School of Medicine, St. Louis (I.P.); Centre Hospitalier Universitaire Sainte-Justine, Montreal (H.B.), and the University of British Columbia, Vancouver General Hospital, Vancouver (J.W.) - both in Canada; the Medical College of Wisconsin, Milwaukee (M.H., S.C.); Stanford Health Care, Stanford (S.A.), and City of Hope Medical Center, Duarte (A.S.) - both in California; Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBiS), CSIC, Universidad de Sevilla, Seville (J.A.P.-S.), Hospital General Universitario Gregorio Marañón, Instituto de Investigación Biomédica Gregorio Marañón, and Universidad Complutense de Madrid, Madrid (M.K.), and Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, Santander (A.B.) - all in Spain; the M.D. Anderson Cancer Center, Houston (A.A.); the James Cancer Hospital and Solove Research Institute and Ohio State University Wexner Medical Center, Columbus (H.C.); Seoul National University College of Internal Medicine, Seoul, South Korea (I.K.); Hôpital Saint-Louis and University Paris Cité, Paris (G.S.); Incyte Corporation, Wilmington, DE (C.T.); and Vanderbilt University Medical Center, Nashville (C.L.K.)
| | - Iskra Pusic
- From University Hospital Regensburg, Regensburg, Germany (D.W.); Dana-Farber Cancer Institute and Harvard Medical School (C.C.) and Massachusetts General Hospital (Z.D.), Boston, and Syndax Pharmaceuticals, Waltham (V.R., T.O., P.O.) - all in Massachusetts; Fred Hutchinson Cancer Center, Seattle (S.J.L.); Washington University School of Medicine, St. Louis (I.P.); Centre Hospitalier Universitaire Sainte-Justine, Montreal (H.B.), and the University of British Columbia, Vancouver General Hospital, Vancouver (J.W.) - both in Canada; the Medical College of Wisconsin, Milwaukee (M.H., S.C.); Stanford Health Care, Stanford (S.A.), and City of Hope Medical Center, Duarte (A.S.) - both in California; Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBiS), CSIC, Universidad de Sevilla, Seville (J.A.P.-S.), Hospital General Universitario Gregorio Marañón, Instituto de Investigación Biomédica Gregorio Marañón, and Universidad Complutense de Madrid, Madrid (M.K.), and Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, Santander (A.B.) - all in Spain; the M.D. Anderson Cancer Center, Houston (A.A.); the James Cancer Hospital and Solove Research Institute and Ohio State University Wexner Medical Center, Columbus (H.C.); Seoul National University College of Internal Medicine, Seoul, South Korea (I.K.); Hôpital Saint-Louis and University Paris Cité, Paris (G.S.); Incyte Corporation, Wilmington, DE (C.T.); and Vanderbilt University Medical Center, Nashville (C.L.K.)
| | - Henrique Bittencourt
- From University Hospital Regensburg, Regensburg, Germany (D.W.); Dana-Farber Cancer Institute and Harvard Medical School (C.C.) and Massachusetts General Hospital (Z.D.), Boston, and Syndax Pharmaceuticals, Waltham (V.R., T.O., P.O.) - all in Massachusetts; Fred Hutchinson Cancer Center, Seattle (S.J.L.); Washington University School of Medicine, St. Louis (I.P.); Centre Hospitalier Universitaire Sainte-Justine, Montreal (H.B.), and the University of British Columbia, Vancouver General Hospital, Vancouver (J.W.) - both in Canada; the Medical College of Wisconsin, Milwaukee (M.H., S.C.); Stanford Health Care, Stanford (S.A.), and City of Hope Medical Center, Duarte (A.S.) - both in California; Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBiS), CSIC, Universidad de Sevilla, Seville (J.A.P.-S.), Hospital General Universitario Gregorio Marañón, Instituto de Investigación Biomédica Gregorio Marañón, and Universidad Complutense de Madrid, Madrid (M.K.), and Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, Santander (A.B.) - all in Spain; the M.D. Anderson Cancer Center, Houston (A.A.); the James Cancer Hospital and Solove Research Institute and Ohio State University Wexner Medical Center, Columbus (H.C.); Seoul National University College of Internal Medicine, Seoul, South Korea (I.K.); Hôpital Saint-Louis and University Paris Cité, Paris (G.S.); Incyte Corporation, Wilmington, DE (C.T.); and Vanderbilt University Medical Center, Nashville (C.L.K.)
| | - Jennifer White
- From University Hospital Regensburg, Regensburg, Germany (D.W.); Dana-Farber Cancer Institute and Harvard Medical School (C.C.) and Massachusetts General Hospital (Z.D.), Boston, and Syndax Pharmaceuticals, Waltham (V.R., T.O., P.O.) - all in Massachusetts; Fred Hutchinson Cancer Center, Seattle (S.J.L.); Washington University School of Medicine, St. Louis (I.P.); Centre Hospitalier Universitaire Sainte-Justine, Montreal (H.B.), and the University of British Columbia, Vancouver General Hospital, Vancouver (J.W.) - both in Canada; the Medical College of Wisconsin, Milwaukee (M.H., S.C.); Stanford Health Care, Stanford (S.A.), and City of Hope Medical Center, Duarte (A.S.) - both in California; Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBiS), CSIC, Universidad de Sevilla, Seville (J.A.P.-S.), Hospital General Universitario Gregorio Marañón, Instituto de Investigación Biomédica Gregorio Marañón, and Universidad Complutense de Madrid, Madrid (M.K.), and Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, Santander (A.B.) - all in Spain; the M.D. Anderson Cancer Center, Houston (A.A.); the James Cancer Hospital and Solove Research Institute and Ohio State University Wexner Medical Center, Columbus (H.C.); Seoul National University College of Internal Medicine, Seoul, South Korea (I.K.); Hôpital Saint-Louis and University Paris Cité, Paris (G.S.); Incyte Corporation, Wilmington, DE (C.T.); and Vanderbilt University Medical Center, Nashville (C.L.K.)
| | - Mehdi Hamadani
- From University Hospital Regensburg, Regensburg, Germany (D.W.); Dana-Farber Cancer Institute and Harvard Medical School (C.C.) and Massachusetts General Hospital (Z.D.), Boston, and Syndax Pharmaceuticals, Waltham (V.R., T.O., P.O.) - all in Massachusetts; Fred Hutchinson Cancer Center, Seattle (S.J.L.); Washington University School of Medicine, St. Louis (I.P.); Centre Hospitalier Universitaire Sainte-Justine, Montreal (H.B.), and the University of British Columbia, Vancouver General Hospital, Vancouver (J.W.) - both in Canada; the Medical College of Wisconsin, Milwaukee (M.H., S.C.); Stanford Health Care, Stanford (S.A.), and City of Hope Medical Center, Duarte (A.S.) - both in California; Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBiS), CSIC, Universidad de Sevilla, Seville (J.A.P.-S.), Hospital General Universitario Gregorio Marañón, Instituto de Investigación Biomédica Gregorio Marañón, and Universidad Complutense de Madrid, Madrid (M.K.), and Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, Santander (A.B.) - all in Spain; the M.D. Anderson Cancer Center, Houston (A.A.); the James Cancer Hospital and Solove Research Institute and Ohio State University Wexner Medical Center, Columbus (H.C.); Seoul National University College of Internal Medicine, Seoul, South Korea (I.K.); Hôpital Saint-Louis and University Paris Cité, Paris (G.S.); Incyte Corporation, Wilmington, DE (C.T.); and Vanderbilt University Medical Center, Nashville (C.L.K.)
| | - Sally Arai
- From University Hospital Regensburg, Regensburg, Germany (D.W.); Dana-Farber Cancer Institute and Harvard Medical School (C.C.) and Massachusetts General Hospital (Z.D.), Boston, and Syndax Pharmaceuticals, Waltham (V.R., T.O., P.O.) - all in Massachusetts; Fred Hutchinson Cancer Center, Seattle (S.J.L.); Washington University School of Medicine, St. Louis (I.P.); Centre Hospitalier Universitaire Sainte-Justine, Montreal (H.B.), and the University of British Columbia, Vancouver General Hospital, Vancouver (J.W.) - both in Canada; the Medical College of Wisconsin, Milwaukee (M.H., S.C.); Stanford Health Care, Stanford (S.A.), and City of Hope Medical Center, Duarte (A.S.) - both in California; Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBiS), CSIC, Universidad de Sevilla, Seville (J.A.P.-S.), Hospital General Universitario Gregorio Marañón, Instituto de Investigación Biomédica Gregorio Marañón, and Universidad Complutense de Madrid, Madrid (M.K.), and Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, Santander (A.B.) - all in Spain; the M.D. Anderson Cancer Center, Houston (A.A.); the James Cancer Hospital and Solove Research Institute and Ohio State University Wexner Medical Center, Columbus (H.C.); Seoul National University College of Internal Medicine, Seoul, South Korea (I.K.); Hôpital Saint-Louis and University Paris Cité, Paris (G.S.); Incyte Corporation, Wilmington, DE (C.T.); and Vanderbilt University Medical Center, Nashville (C.L.K.)
| | - Amandeep Salhotra
- From University Hospital Regensburg, Regensburg, Germany (D.W.); Dana-Farber Cancer Institute and Harvard Medical School (C.C.) and Massachusetts General Hospital (Z.D.), Boston, and Syndax Pharmaceuticals, Waltham (V.R., T.O., P.O.) - all in Massachusetts; Fred Hutchinson Cancer Center, Seattle (S.J.L.); Washington University School of Medicine, St. Louis (I.P.); Centre Hospitalier Universitaire Sainte-Justine, Montreal (H.B.), and the University of British Columbia, Vancouver General Hospital, Vancouver (J.W.) - both in Canada; the Medical College of Wisconsin, Milwaukee (M.H., S.C.); Stanford Health Care, Stanford (S.A.), and City of Hope Medical Center, Duarte (A.S.) - both in California; Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBiS), CSIC, Universidad de Sevilla, Seville (J.A.P.-S.), Hospital General Universitario Gregorio Marañón, Instituto de Investigación Biomédica Gregorio Marañón, and Universidad Complutense de Madrid, Madrid (M.K.), and Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, Santander (A.B.) - all in Spain; the M.D. Anderson Cancer Center, Houston (A.A.); the James Cancer Hospital and Solove Research Institute and Ohio State University Wexner Medical Center, Columbus (H.C.); Seoul National University College of Internal Medicine, Seoul, South Korea (I.K.); Hôpital Saint-Louis and University Paris Cité, Paris (G.S.); Incyte Corporation, Wilmington, DE (C.T.); and Vanderbilt University Medical Center, Nashville (C.L.K.)
| | - Jose A Perez-Simon
- From University Hospital Regensburg, Regensburg, Germany (D.W.); Dana-Farber Cancer Institute and Harvard Medical School (C.C.) and Massachusetts General Hospital (Z.D.), Boston, and Syndax Pharmaceuticals, Waltham (V.R., T.O., P.O.) - all in Massachusetts; Fred Hutchinson Cancer Center, Seattle (S.J.L.); Washington University School of Medicine, St. Louis (I.P.); Centre Hospitalier Universitaire Sainte-Justine, Montreal (H.B.), and the University of British Columbia, Vancouver General Hospital, Vancouver (J.W.) - both in Canada; the Medical College of Wisconsin, Milwaukee (M.H., S.C.); Stanford Health Care, Stanford (S.A.), and City of Hope Medical Center, Duarte (A.S.) - both in California; Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBiS), CSIC, Universidad de Sevilla, Seville (J.A.P.-S.), Hospital General Universitario Gregorio Marañón, Instituto de Investigación Biomédica Gregorio Marañón, and Universidad Complutense de Madrid, Madrid (M.K.), and Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, Santander (A.B.) - all in Spain; the M.D. Anderson Cancer Center, Houston (A.A.); the James Cancer Hospital and Solove Research Institute and Ohio State University Wexner Medical Center, Columbus (H.C.); Seoul National University College of Internal Medicine, Seoul, South Korea (I.K.); Hôpital Saint-Louis and University Paris Cité, Paris (G.S.); Incyte Corporation, Wilmington, DE (C.T.); and Vanderbilt University Medical Center, Nashville (C.L.K.)
| | - Amin Alousi
- From University Hospital Regensburg, Regensburg, Germany (D.W.); Dana-Farber Cancer Institute and Harvard Medical School (C.C.) and Massachusetts General Hospital (Z.D.), Boston, and Syndax Pharmaceuticals, Waltham (V.R., T.O., P.O.) - all in Massachusetts; Fred Hutchinson Cancer Center, Seattle (S.J.L.); Washington University School of Medicine, St. Louis (I.P.); Centre Hospitalier Universitaire Sainte-Justine, Montreal (H.B.), and the University of British Columbia, Vancouver General Hospital, Vancouver (J.W.) - both in Canada; the Medical College of Wisconsin, Milwaukee (M.H., S.C.); Stanford Health Care, Stanford (S.A.), and City of Hope Medical Center, Duarte (A.S.) - both in California; Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBiS), CSIC, Universidad de Sevilla, Seville (J.A.P.-S.), Hospital General Universitario Gregorio Marañón, Instituto de Investigación Biomédica Gregorio Marañón, and Universidad Complutense de Madrid, Madrid (M.K.), and Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, Santander (A.B.) - all in Spain; the M.D. Anderson Cancer Center, Houston (A.A.); the James Cancer Hospital and Solove Research Institute and Ohio State University Wexner Medical Center, Columbus (H.C.); Seoul National University College of Internal Medicine, Seoul, South Korea (I.K.); Hôpital Saint-Louis and University Paris Cité, Paris (G.S.); Incyte Corporation, Wilmington, DE (C.T.); and Vanderbilt University Medical Center, Nashville (C.L.K.)
| | - Hannah Choe
- From University Hospital Regensburg, Regensburg, Germany (D.W.); Dana-Farber Cancer Institute and Harvard Medical School (C.C.) and Massachusetts General Hospital (Z.D.), Boston, and Syndax Pharmaceuticals, Waltham (V.R., T.O., P.O.) - all in Massachusetts; Fred Hutchinson Cancer Center, Seattle (S.J.L.); Washington University School of Medicine, St. Louis (I.P.); Centre Hospitalier Universitaire Sainte-Justine, Montreal (H.B.), and the University of British Columbia, Vancouver General Hospital, Vancouver (J.W.) - both in Canada; the Medical College of Wisconsin, Milwaukee (M.H., S.C.); Stanford Health Care, Stanford (S.A.), and City of Hope Medical Center, Duarte (A.S.) - both in California; Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBiS), CSIC, Universidad de Sevilla, Seville (J.A.P.-S.), Hospital General Universitario Gregorio Marañón, Instituto de Investigación Biomédica Gregorio Marañón, and Universidad Complutense de Madrid, Madrid (M.K.), and Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, Santander (A.B.) - all in Spain; the M.D. Anderson Cancer Center, Houston (A.A.); the James Cancer Hospital and Solove Research Institute and Ohio State University Wexner Medical Center, Columbus (H.C.); Seoul National University College of Internal Medicine, Seoul, South Korea (I.K.); Hôpital Saint-Louis and University Paris Cité, Paris (G.S.); Incyte Corporation, Wilmington, DE (C.T.); and Vanderbilt University Medical Center, Nashville (C.L.K.)
| | - Mi Kwon
- From University Hospital Regensburg, Regensburg, Germany (D.W.); Dana-Farber Cancer Institute and Harvard Medical School (C.C.) and Massachusetts General Hospital (Z.D.), Boston, and Syndax Pharmaceuticals, Waltham (V.R., T.O., P.O.) - all in Massachusetts; Fred Hutchinson Cancer Center, Seattle (S.J.L.); Washington University School of Medicine, St. Louis (I.P.); Centre Hospitalier Universitaire Sainte-Justine, Montreal (H.B.), and the University of British Columbia, Vancouver General Hospital, Vancouver (J.W.) - both in Canada; the Medical College of Wisconsin, Milwaukee (M.H., S.C.); Stanford Health Care, Stanford (S.A.), and City of Hope Medical Center, Duarte (A.S.) - both in California; Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBiS), CSIC, Universidad de Sevilla, Seville (J.A.P.-S.), Hospital General Universitario Gregorio Marañón, Instituto de Investigación Biomédica Gregorio Marañón, and Universidad Complutense de Madrid, Madrid (M.K.), and Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, Santander (A.B.) - all in Spain; the M.D. Anderson Cancer Center, Houston (A.A.); the James Cancer Hospital and Solove Research Institute and Ohio State University Wexner Medical Center, Columbus (H.C.); Seoul National University College of Internal Medicine, Seoul, South Korea (I.K.); Hôpital Saint-Louis and University Paris Cité, Paris (G.S.); Incyte Corporation, Wilmington, DE (C.T.); and Vanderbilt University Medical Center, Nashville (C.L.K.)
| | - Arancha Bermúdez
- From University Hospital Regensburg, Regensburg, Germany (D.W.); Dana-Farber Cancer Institute and Harvard Medical School (C.C.) and Massachusetts General Hospital (Z.D.), Boston, and Syndax Pharmaceuticals, Waltham (V.R., T.O., P.O.) - all in Massachusetts; Fred Hutchinson Cancer Center, Seattle (S.J.L.); Washington University School of Medicine, St. Louis (I.P.); Centre Hospitalier Universitaire Sainte-Justine, Montreal (H.B.), and the University of British Columbia, Vancouver General Hospital, Vancouver (J.W.) - both in Canada; the Medical College of Wisconsin, Milwaukee (M.H., S.C.); Stanford Health Care, Stanford (S.A.), and City of Hope Medical Center, Duarte (A.S.) - both in California; Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBiS), CSIC, Universidad de Sevilla, Seville (J.A.P.-S.), Hospital General Universitario Gregorio Marañón, Instituto de Investigación Biomédica Gregorio Marañón, and Universidad Complutense de Madrid, Madrid (M.K.), and Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, Santander (A.B.) - all in Spain; the M.D. Anderson Cancer Center, Houston (A.A.); the James Cancer Hospital and Solove Research Institute and Ohio State University Wexner Medical Center, Columbus (H.C.); Seoul National University College of Internal Medicine, Seoul, South Korea (I.K.); Hôpital Saint-Louis and University Paris Cité, Paris (G.S.); Incyte Corporation, Wilmington, DE (C.T.); and Vanderbilt University Medical Center, Nashville (C.L.K.)
| | - Inho Kim
- From University Hospital Regensburg, Regensburg, Germany (D.W.); Dana-Farber Cancer Institute and Harvard Medical School (C.C.) and Massachusetts General Hospital (Z.D.), Boston, and Syndax Pharmaceuticals, Waltham (V.R., T.O., P.O.) - all in Massachusetts; Fred Hutchinson Cancer Center, Seattle (S.J.L.); Washington University School of Medicine, St. Louis (I.P.); Centre Hospitalier Universitaire Sainte-Justine, Montreal (H.B.), and the University of British Columbia, Vancouver General Hospital, Vancouver (J.W.) - both in Canada; the Medical College of Wisconsin, Milwaukee (M.H., S.C.); Stanford Health Care, Stanford (S.A.), and City of Hope Medical Center, Duarte (A.S.) - both in California; Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBiS), CSIC, Universidad de Sevilla, Seville (J.A.P.-S.), Hospital General Universitario Gregorio Marañón, Instituto de Investigación Biomédica Gregorio Marañón, and Universidad Complutense de Madrid, Madrid (M.K.), and Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, Santander (A.B.) - all in Spain; the M.D. Anderson Cancer Center, Houston (A.A.); the James Cancer Hospital and Solove Research Institute and Ohio State University Wexner Medical Center, Columbus (H.C.); Seoul National University College of Internal Medicine, Seoul, South Korea (I.K.); Hôpital Saint-Louis and University Paris Cité, Paris (G.S.); Incyte Corporation, Wilmington, DE (C.T.); and Vanderbilt University Medical Center, Nashville (C.L.K.)
| | - Gerard Socié
- From University Hospital Regensburg, Regensburg, Germany (D.W.); Dana-Farber Cancer Institute and Harvard Medical School (C.C.) and Massachusetts General Hospital (Z.D.), Boston, and Syndax Pharmaceuticals, Waltham (V.R., T.O., P.O.) - all in Massachusetts; Fred Hutchinson Cancer Center, Seattle (S.J.L.); Washington University School of Medicine, St. Louis (I.P.); Centre Hospitalier Universitaire Sainte-Justine, Montreal (H.B.), and the University of British Columbia, Vancouver General Hospital, Vancouver (J.W.) - both in Canada; the Medical College of Wisconsin, Milwaukee (M.H., S.C.); Stanford Health Care, Stanford (S.A.), and City of Hope Medical Center, Duarte (A.S.) - both in California; Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBiS), CSIC, Universidad de Sevilla, Seville (J.A.P.-S.), Hospital General Universitario Gregorio Marañón, Instituto de Investigación Biomédica Gregorio Marañón, and Universidad Complutense de Madrid, Madrid (M.K.), and Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, Santander (A.B.) - all in Spain; the M.D. Anderson Cancer Center, Houston (A.A.); the James Cancer Hospital and Solove Research Institute and Ohio State University Wexner Medical Center, Columbus (H.C.); Seoul National University College of Internal Medicine, Seoul, South Korea (I.K.); Hôpital Saint-Louis and University Paris Cité, Paris (G.S.); Incyte Corporation, Wilmington, DE (C.T.); and Vanderbilt University Medical Center, Nashville (C.L.K.)
| | - Saurabh Chhabra
- From University Hospital Regensburg, Regensburg, Germany (D.W.); Dana-Farber Cancer Institute and Harvard Medical School (C.C.) and Massachusetts General Hospital (Z.D.), Boston, and Syndax Pharmaceuticals, Waltham (V.R., T.O., P.O.) - all in Massachusetts; Fred Hutchinson Cancer Center, Seattle (S.J.L.); Washington University School of Medicine, St. Louis (I.P.); Centre Hospitalier Universitaire Sainte-Justine, Montreal (H.B.), and the University of British Columbia, Vancouver General Hospital, Vancouver (J.W.) - both in Canada; the Medical College of Wisconsin, Milwaukee (M.H., S.C.); Stanford Health Care, Stanford (S.A.), and City of Hope Medical Center, Duarte (A.S.) - both in California; Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBiS), CSIC, Universidad de Sevilla, Seville (J.A.P.-S.), Hospital General Universitario Gregorio Marañón, Instituto de Investigación Biomédica Gregorio Marañón, and Universidad Complutense de Madrid, Madrid (M.K.), and Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, Santander (A.B.) - all in Spain; the M.D. Anderson Cancer Center, Houston (A.A.); the James Cancer Hospital and Solove Research Institute and Ohio State University Wexner Medical Center, Columbus (H.C.); Seoul National University College of Internal Medicine, Seoul, South Korea (I.K.); Hôpital Saint-Louis and University Paris Cité, Paris (G.S.); Incyte Corporation, Wilmington, DE (C.T.); and Vanderbilt University Medical Center, Nashville (C.L.K.)
| | - Vedran Radojcic
- From University Hospital Regensburg, Regensburg, Germany (D.W.); Dana-Farber Cancer Institute and Harvard Medical School (C.C.) and Massachusetts General Hospital (Z.D.), Boston, and Syndax Pharmaceuticals, Waltham (V.R., T.O., P.O.) - all in Massachusetts; Fred Hutchinson Cancer Center, Seattle (S.J.L.); Washington University School of Medicine, St. Louis (I.P.); Centre Hospitalier Universitaire Sainte-Justine, Montreal (H.B.), and the University of British Columbia, Vancouver General Hospital, Vancouver (J.W.) - both in Canada; the Medical College of Wisconsin, Milwaukee (M.H., S.C.); Stanford Health Care, Stanford (S.A.), and City of Hope Medical Center, Duarte (A.S.) - both in California; Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBiS), CSIC, Universidad de Sevilla, Seville (J.A.P.-S.), Hospital General Universitario Gregorio Marañón, Instituto de Investigación Biomédica Gregorio Marañón, and Universidad Complutense de Madrid, Madrid (M.K.), and Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, Santander (A.B.) - all in Spain; the M.D. Anderson Cancer Center, Houston (A.A.); the James Cancer Hospital and Solove Research Institute and Ohio State University Wexner Medical Center, Columbus (H.C.); Seoul National University College of Internal Medicine, Seoul, South Korea (I.K.); Hôpital Saint-Louis and University Paris Cité, Paris (G.S.); Incyte Corporation, Wilmington, DE (C.T.); and Vanderbilt University Medical Center, Nashville (C.L.K.)
| | - Timothy O'Toole
- From University Hospital Regensburg, Regensburg, Germany (D.W.); Dana-Farber Cancer Institute and Harvard Medical School (C.C.) and Massachusetts General Hospital (Z.D.), Boston, and Syndax Pharmaceuticals, Waltham (V.R., T.O., P.O.) - all in Massachusetts; Fred Hutchinson Cancer Center, Seattle (S.J.L.); Washington University School of Medicine, St. Louis (I.P.); Centre Hospitalier Universitaire Sainte-Justine, Montreal (H.B.), and the University of British Columbia, Vancouver General Hospital, Vancouver (J.W.) - both in Canada; the Medical College of Wisconsin, Milwaukee (M.H., S.C.); Stanford Health Care, Stanford (S.A.), and City of Hope Medical Center, Duarte (A.S.) - both in California; Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBiS), CSIC, Universidad de Sevilla, Seville (J.A.P.-S.), Hospital General Universitario Gregorio Marañón, Instituto de Investigación Biomédica Gregorio Marañón, and Universidad Complutense de Madrid, Madrid (M.K.), and Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, Santander (A.B.) - all in Spain; the M.D. Anderson Cancer Center, Houston (A.A.); the James Cancer Hospital and Solove Research Institute and Ohio State University Wexner Medical Center, Columbus (H.C.); Seoul National University College of Internal Medicine, Seoul, South Korea (I.K.); Hôpital Saint-Louis and University Paris Cité, Paris (G.S.); Incyte Corporation, Wilmington, DE (C.T.); and Vanderbilt University Medical Center, Nashville (C.L.K.)
| | - Chuan Tian
- From University Hospital Regensburg, Regensburg, Germany (D.W.); Dana-Farber Cancer Institute and Harvard Medical School (C.C.) and Massachusetts General Hospital (Z.D.), Boston, and Syndax Pharmaceuticals, Waltham (V.R., T.O., P.O.) - all in Massachusetts; Fred Hutchinson Cancer Center, Seattle (S.J.L.); Washington University School of Medicine, St. Louis (I.P.); Centre Hospitalier Universitaire Sainte-Justine, Montreal (H.B.), and the University of British Columbia, Vancouver General Hospital, Vancouver (J.W.) - both in Canada; the Medical College of Wisconsin, Milwaukee (M.H., S.C.); Stanford Health Care, Stanford (S.A.), and City of Hope Medical Center, Duarte (A.S.) - both in California; Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBiS), CSIC, Universidad de Sevilla, Seville (J.A.P.-S.), Hospital General Universitario Gregorio Marañón, Instituto de Investigación Biomédica Gregorio Marañón, and Universidad Complutense de Madrid, Madrid (M.K.), and Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, Santander (A.B.) - all in Spain; the M.D. Anderson Cancer Center, Houston (A.A.); the James Cancer Hospital and Solove Research Institute and Ohio State University Wexner Medical Center, Columbus (H.C.); Seoul National University College of Internal Medicine, Seoul, South Korea (I.K.); Hôpital Saint-Louis and University Paris Cité, Paris (G.S.); Incyte Corporation, Wilmington, DE (C.T.); and Vanderbilt University Medical Center, Nashville (C.L.K.)
| | - Peter Ordentlich
- From University Hospital Regensburg, Regensburg, Germany (D.W.); Dana-Farber Cancer Institute and Harvard Medical School (C.C.) and Massachusetts General Hospital (Z.D.), Boston, and Syndax Pharmaceuticals, Waltham (V.R., T.O., P.O.) - all in Massachusetts; Fred Hutchinson Cancer Center, Seattle (S.J.L.); Washington University School of Medicine, St. Louis (I.P.); Centre Hospitalier Universitaire Sainte-Justine, Montreal (H.B.), and the University of British Columbia, Vancouver General Hospital, Vancouver (J.W.) - both in Canada; the Medical College of Wisconsin, Milwaukee (M.H., S.C.); Stanford Health Care, Stanford (S.A.), and City of Hope Medical Center, Duarte (A.S.) - both in California; Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBiS), CSIC, Universidad de Sevilla, Seville (J.A.P.-S.), Hospital General Universitario Gregorio Marañón, Instituto de Investigación Biomédica Gregorio Marañón, and Universidad Complutense de Madrid, Madrid (M.K.), and Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, Santander (A.B.) - all in Spain; the M.D. Anderson Cancer Center, Houston (A.A.); the James Cancer Hospital and Solove Research Institute and Ohio State University Wexner Medical Center, Columbus (H.C.); Seoul National University College of Internal Medicine, Seoul, South Korea (I.K.); Hôpital Saint-Louis and University Paris Cité, Paris (G.S.); Incyte Corporation, Wilmington, DE (C.T.); and Vanderbilt University Medical Center, Nashville (C.L.K.)
| | - Zachariah DeFilipp
- From University Hospital Regensburg, Regensburg, Germany (D.W.); Dana-Farber Cancer Institute and Harvard Medical School (C.C.) and Massachusetts General Hospital (Z.D.), Boston, and Syndax Pharmaceuticals, Waltham (V.R., T.O., P.O.) - all in Massachusetts; Fred Hutchinson Cancer Center, Seattle (S.J.L.); Washington University School of Medicine, St. Louis (I.P.); Centre Hospitalier Universitaire Sainte-Justine, Montreal (H.B.), and the University of British Columbia, Vancouver General Hospital, Vancouver (J.W.) - both in Canada; the Medical College of Wisconsin, Milwaukee (M.H., S.C.); Stanford Health Care, Stanford (S.A.), and City of Hope Medical Center, Duarte (A.S.) - both in California; Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBiS), CSIC, Universidad de Sevilla, Seville (J.A.P.-S.), Hospital General Universitario Gregorio Marañón, Instituto de Investigación Biomédica Gregorio Marañón, and Universidad Complutense de Madrid, Madrid (M.K.), and Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, Santander (A.B.) - all in Spain; the M.D. Anderson Cancer Center, Houston (A.A.); the James Cancer Hospital and Solove Research Institute and Ohio State University Wexner Medical Center, Columbus (H.C.); Seoul National University College of Internal Medicine, Seoul, South Korea (I.K.); Hôpital Saint-Louis and University Paris Cité, Paris (G.S.); Incyte Corporation, Wilmington, DE (C.T.); and Vanderbilt University Medical Center, Nashville (C.L.K.)
| | - Carrie L Kitko
- From University Hospital Regensburg, Regensburg, Germany (D.W.); Dana-Farber Cancer Institute and Harvard Medical School (C.C.) and Massachusetts General Hospital (Z.D.), Boston, and Syndax Pharmaceuticals, Waltham (V.R., T.O., P.O.) - all in Massachusetts; Fred Hutchinson Cancer Center, Seattle (S.J.L.); Washington University School of Medicine, St. Louis (I.P.); Centre Hospitalier Universitaire Sainte-Justine, Montreal (H.B.), and the University of British Columbia, Vancouver General Hospital, Vancouver (J.W.) - both in Canada; the Medical College of Wisconsin, Milwaukee (M.H., S.C.); Stanford Health Care, Stanford (S.A.), and City of Hope Medical Center, Duarte (A.S.) - both in California; Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBiS), CSIC, Universidad de Sevilla, Seville (J.A.P.-S.), Hospital General Universitario Gregorio Marañón, Instituto de Investigación Biomédica Gregorio Marañón, and Universidad Complutense de Madrid, Madrid (M.K.), and Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, Santander (A.B.) - all in Spain; the M.D. Anderson Cancer Center, Houston (A.A.); the James Cancer Hospital and Solove Research Institute and Ohio State University Wexner Medical Center, Columbus (H.C.); Seoul National University College of Internal Medicine, Seoul, South Korea (I.K.); Hôpital Saint-Louis and University Paris Cité, Paris (G.S.); Incyte Corporation, Wilmington, DE (C.T.); and Vanderbilt University Medical Center, Nashville (C.L.K.)
| |
Collapse
|
|
6
|
Vijayan V, Yan H, Lohmeyer JK, Prentiss KA, Patil RV, Barbarito G, Lopez I, Elezaby A, Peterson K, Baker J, Ostberg NP, Bertaina A, Negrin RS, Mochly-Rosen D, Weinberg K, Haileselassie B. Extracellular release of damaged mitochondria induced by prehematopoietic stem cell transplant conditioning exacerbates GVHD. Blood Adv 2024; 8:3691-3704. [PMID: 38701354 PMCID: PMC11284707 DOI: 10.1182/bloodadvances.2023012328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 03/07/2024] [Accepted: 04/12/2024] [Indexed: 05/05/2024] Open
Abstract
ABSTRACT Despite therapeutic advancements, graft-versus-host disease (GVHD) is a major complication of hematopoietic stem cell transplantation (HSCT). In current models of GVHD, tissue injury induced by cytotoxic conditioning regimens, along with translocation of microbes expressing pathogen-associated molecular patterns, result in activation of host antigen-presenting cells (APCs) to stimulate alloreactive donor T lymphocytes. Recent studies have demonstrated that in many pathologic states, tissue injury results in the release of mitochondria from the cytoplasm to the extracellular space. We hypothesized that extracellular mitochondria, which are related to archaebacteria, could also trigger GVHD by stimulation of host APCs. We found that clinically relevant doses of radiation or busulfan induced extracellular release of mitochondria by various cell types, including cultured intestinal epithelial cells. Conditioning-mediated mitochondrial release was associated with mitochondrial damage and impaired quality control but did not affect the viability of the cells. Extracellular mitochondria directly stimulated host APCs to express higher levels of major histocompatibility complex II (MHC-II), costimulatory CD86, and proinflammatory cytokines, resulting in increased donor T-cell activation, and proliferation in mixed lymphocyte reactions. Analyses of plasma from both experimental mice and a cohort of children undergoing HSCT demonstrated that conditioning induced extracellular mitochondrial release in vivo. In mice undergoing MHC-mismatched HSCT, administration of purified syngeneic extracellular mitochondria increased host APC activation and exacerbated GVHD. Our data suggest that pre-HSCT conditioning results in extracellular release of damaged mitochondria, which increase alloreactivity and exacerbate GVHD. Therefore, decreasing the extracellular release of damaged mitochondria after conditioning could serve as a novel strategy for GVHD prevention.
Collapse
Affiliation(s)
- Vijith Vijayan
- Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| | - Hao Yan
- Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Juliane K. Lohmeyer
- Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Kaylin A. Prentiss
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| | - Rachna V. Patil
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| | - Giulia Barbarito
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| | - Ivan Lopez
- Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| | - Aly Elezaby
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA
| | - Kolten Peterson
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| | - Jeanette Baker
- Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Nicolai P. Ostberg
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA
| | - Alice Bertaina
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| | - Robert S. Negrin
- Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Daria Mochly-Rosen
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA
| | - Kenneth Weinberg
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| | - Bereketeab Haileselassie
- Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| |
Collapse
|
|
7
|
He J, Zheng F, Zhang L, Cai J, Ogawa Y, Tsubota K, Liu S, Jin X. Single-cell RNA-sequencing reveals the transcriptional landscape of lacrimal gland in GVHD mouse model. Ocul Surf 2024; 33:50-63. [PMID: 38703817 DOI: 10.1016/j.jtos.2024.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 04/02/2024] [Accepted: 04/26/2024] [Indexed: 05/06/2024]
Abstract
PURPOSE To investigate the global transcriptional landscape of lacrimal gland cell populations in the GVHD mouse model. METHODS Single-cell RNA sequencing and further bioinformatic analysis of dissociated lacrimal gland (LG) cells from the mouse model were performed. Parts of transcriptional results were confirmed by immunofluorescence staining. RESULTS We identified 23 cell populations belonging to 11 cell types. In GVHD LG, the proportion of acinar cells, myoepithelial cells, and endothelial cells was remarkably decreased, while T cells and macrophages were significantly expanded. Gene expression analysis indicated decreased secretion function, extracellular matrix (ECM) synthesis, and increased chemokines of myoepithelial cells. A newly described epithelial population named Lrg1high epithelial cells, expressing distinct gene signatures, was exclusively identified in GVHD LG. The fibroblasts exhibited an inflammation gene pattern. The gene pattern of endothelial cells suggested an increased ability to recruit immune cells and damaged cell-cell junctions. T cells were mainly comprised of Th2 cells and effective memory CD8+ T cells. GVHD macrophages exhibited a Th2 cell-linked pattern. CONCLUSIONS This single-cell atlas uncovered alterations of proportion and gene expression patterns of cell populations and constructed cell-cell communication networks of GVHD LG. These data may provide some new insight into understanding the development of ocular GVHD.
Collapse
Affiliation(s)
- Jingliang He
- Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, China; Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, China; Zhejiang Provincial Engineering Institute on Eye Diseases, Hangzhou, Zhejiang, China
| | - Fang Zheng
- Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, China; Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, China; Zhejiang Provincial Engineering Institute on Eye Diseases, Hangzhou, Zhejiang, China
| | - Li Zhang
- Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, China; Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, China; Zhejiang Provincial Engineering Institute on Eye Diseases, Hangzhou, Zhejiang, China
| | | | - Yoko Ogawa
- Department of Ophthalmology, Keio University, School of Medicine, Tokyo, Japan
| | - Kazuo Tsubota
- Department of Ophthalmology, Keio University, School of Medicine, Tokyo, Japan; Tsubota Laboratory, Inc., Tokyo, Japan
| | - Shan Liu
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China
| | - Xiuming Jin
- Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, China; Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, China; Zhejiang Provincial Engineering Institute on Eye Diseases, Hangzhou, Zhejiang, China.
| |
Collapse
|
|
8
|
Adams RC, Carter-Cusack D, Llanes GT, Hunter CR, Vinnakota JM, Ruitenberg MJ, Vukovic J, Bertolino P, Chand KK, Wixey JA, Nayler SP, Hill GR, Furlan SN, Zeiser R, MacDonald KPA. CSF1R inhibition promotes neuroinflammation and behavioral deficits during graft-versus-host disease in mice. Blood 2024; 143:912-929. [PMID: 38048572 DOI: 10.1182/blood.2023022040] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 10/31/2023] [Accepted: 11/13/2023] [Indexed: 12/06/2023] Open
Abstract
ABSTRACT Chronic graft-versus-host disease (cGVHD) remains a significant complication of allogeneic hematopoietic stem cell transplantation. Central nervous system (CNS) involvement is becoming increasingly recognized, in which brain-infiltrating donor major histocompatibility complex (MHC) class II+ bone marrow-derived macrophages (BMDM) drive pathology. BMDM are also mediators of cutaneous and pulmonary cGVHD, and clinical trials assessing the efficacy of antibody blockade of colony-stimulating factor 1 receptor (CSF1R) to deplete macrophages are promising. We hypothesized that CSF1R antibody blockade may also be a useful strategy to prevent/treat CNS cGVHD. Increased blood-brain barrier permeability during acute GVHD (aGVHD) facilitated CNS antibody access and microglia depletion by anti-CSF1R treatment. However, CSF1R blockade early after transplant unexpectedly exacerbated aGVHD neuroinflammation. In established cGVHD, vascular changes and anti-CSF1R efficacy were more limited. Anti-CSF1R-treated mice retained donor BMDM, activated microglia, CD8+ and CD4+ T cells, and local cytokine expression in the brain. These findings were recapitulated in GVHD recipients, in which CSF1R was conditionally depleted in donor CX3CR1+ BMDM. Notably, inhibition of CSF1R signaling after transplant failed to reverse GVHD-induced behavioral changes. Moreover, we observed aberrant behavior in non-GVHD control recipients administered anti-CSF1R blocking antibody and naïve mice lacking CSF1R in CX3CR1+ cells, revealing a novel role for homeostatic microglia and indicating that ongoing clinical trials of CSF1R inhibition should assess neurological adverse events in patients. In contrast, transfer of Ifngr-/- grafts could reduce MHC class II+ BMDM infiltration, resulting in improved neurocognitive function. Our findings highlight unexpected neurological immune toxicity during CSF1R blockade and provide alternative targets for the treatment of cGVHD within the CNS.
Collapse
Affiliation(s)
- Rachael C Adams
- Infection and Inflammation Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
- Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
- Department of Medicine I, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Dylan Carter-Cusack
- Infection and Inflammation Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Genesis T Llanes
- Infection and Inflammation Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Christopher R Hunter
- Infection and Inflammation Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Janaki Manoja Vinnakota
- Department of Medicine I, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Faculty of Biology, Albert-Ludwigs University, Freiburg, Germany
| | - Marc J Ruitenberg
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Jana Vukovic
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Patrick Bertolino
- Centenary Institute and University of Sydney, AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Kirat K Chand
- UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Julie A Wixey
- UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
- Perinatal Research Centre, Royal Brisbane and Women's Hospital, Herston, Brisbane, QLD, Australia
| | - Samuel P Nayler
- Infection and Inflammation Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Geoffrey R Hill
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA
- Division of Oncology, Department of Medicine, University of Washington, Seattle, WA
| | - Scott N Furlan
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA
| | - Robert Zeiser
- Department of Medicine I, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany
- German Cancer Consortium, Partner Site Freiburg, Freiburg, Germany, and German Cancer Research Centre, Heidelberg, Germany
| | - Kelli P A MacDonald
- Infection and Inflammation Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| |
Collapse
|
|
9
|
Shaikh SN, Willis EF, Dierich M, Xu Y, Stuart SJS, Gobe GC, Bashaw AA, Rawashdeh O, Kim SJ, Vukovic J. CSF-1R inhibitor PLX3397 attenuates peripheral and brain chronic GVHD and improves functional outcomes in mice. J Neuroinflammation 2023; 20:300. [PMID: 38102698 PMCID: PMC10725001 DOI: 10.1186/s12974-023-02984-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 12/03/2023] [Indexed: 12/17/2023] Open
Abstract
Graft-versus-host disease (GVHD) is a serious complication of otherwise curative allogeneic haematopoietic stem cell transplants. Chronic GVHD induces pathological changes in peripheral organs as well as the brain and is a frequent cause of late morbidity and death after bone-marrow transplantation. In the periphery, bone-marrow-derived macrophages are key drivers of pathology, but recent evidence suggests that these cells also infiltrate into cGVHD-affected brains. Microglia are also persistently activated in the cGVHD-affected brain. To understand the involvement of these myeloid cell populations in the development and/or progression of cGVHD pathology, we here utilized the blood-brain-barrier permeable colony stimulating factor-1 receptor (CSF-1R) inhibitor PLX3397 (pexidartinib) at varying doses to pharmacologically deplete both cell types. We demonstrate that PLX3397 treatment during the development of cGVHD (i.e., 30 days post-transplant) improves disease symptoms, reducing both the clinical scores and histopathology of multiple cGVHD target organs, including the sequestration of T cells in cGVHD-affected skin tissue. Cognitive impairments associated with cGVHD and neuroinflammation were also attenuated by PLX3397 treatment. PLX3397 treatment prior to the onset of cGVHD (i.e., immediately post-transplant) did not change in clinical scores or histopathology. Overall, our data demonstrate significant benefits of using PLX3397 for the treatment of cGVHD and associated organ pathologies in both the periphery and brain, highlighting the therapeutic potential of pexidartinib for this condition.
Collapse
Affiliation(s)
- Samreen N Shaikh
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia
| | - Emily F Willis
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia
| | - Max Dierich
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia
| | - Yi Xu
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia
| | - Samuel J S Stuart
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia
| | - Glenda C Gobe
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia
| | - Abate A Bashaw
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia
| | - Oliver Rawashdeh
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia
| | - Seung Jae Kim
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia
| | - Jana Vukovic
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia.
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
| |
Collapse
|
|
10
|
Kandalla PK, Subburayalu J, Cocita C, de Laval B, Tomasello E, Iacono J, Nitsche J, Canali MM, Cathou W, Bessou G, Mossadegh‐Keller N, Huber C, Mouchiroud G, Bourette RP, Grasset M, Bornhäuser M, Sarrazin S, Dalod M, Sieweke MH. M-CSF directs myeloid and NK cell differentiation to protect from CMV after hematopoietic cell transplantation. EMBO Mol Med 2023; 15:e17694. [PMID: 37635627 PMCID: PMC10630876 DOI: 10.15252/emmm.202317694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 07/25/2023] [Accepted: 07/25/2023] [Indexed: 08/29/2023] Open
Abstract
Therapies reconstituting autologous antiviral immunocompetence may represent an important prophylaxis and treatment for immunosuppressed individuals. Following hematopoietic cell transplantation (HCT), patients are susceptible to Herpesviridae including cytomegalovirus (CMV). We show in a murine model of HCT that macrophage colony-stimulating factor (M-CSF) promoted rapid antiviral activity and protection from viremia caused by murine CMV. M-CSF given at transplantation stimulated sequential myeloid and natural killer (NK) cell differentiation culminating in increased NK cell numbers, production of granzyme B and interferon-γ. This depended upon M-CSF-induced myelopoiesis leading to IL15Rα-mediated presentation of IL-15 on monocytes, augmented by type I interferons from plasmacytoid dendritic cells. Demonstrating relevance to human HCT, M-CSF induced myelomonocytic IL15Rα expression and numbers of functional NK cells in G-CSF-mobilized hematopoietic stem and progenitor cells. Together, M-CSF-induced myelopoiesis triggered an integrated differentiation of myeloid and NK cells to protect HCT recipients from CMV. Thus, our results identify a rationale for the therapeutic use of M-CSF to rapidly reconstitute antiviral activity in immunocompromised individuals, which may provide a general paradigm to boost innate antiviral immunocompetence using host-directed therapies.
Collapse
Affiliation(s)
- Prashanth K Kandalla
- Center for Regenerative Therapies Dresden (CRTD)Technical University DresdenDresdenGermany
- Aix Marseille University, CNRS, INSERMCIMLMarseilleFrance
| | - Julien Subburayalu
- Center for Regenerative Therapies Dresden (CRTD)Technical University DresdenDresdenGermany
- Department of Internal Medicine IUniversity Hospital Carl Gustav Carus DresdenDresdenGermany
| | - Clément Cocita
- Aix Marseille University, CNRS, INSERMCIMLMarseilleFrance
- Aix‐Marseille University, CNRS, INSERMCIML, Turing Center for Living SystemsMarseilleFrance
| | | | - Elena Tomasello
- Aix Marseille University, CNRS, INSERMCIMLMarseilleFrance
- Aix‐Marseille University, CNRS, INSERMCIML, Turing Center for Living SystemsMarseilleFrance
| | - Johanna Iacono
- Aix Marseille University, CNRS, INSERMCIMLMarseilleFrance
| | - Jessica Nitsche
- Center for Regenerative Therapies Dresden (CRTD)Technical University DresdenDresdenGermany
| | - Maria M Canali
- Aix Marseille University, CNRS, INSERMCIMLMarseilleFrance
| | | | - Gilles Bessou
- Aix Marseille University, CNRS, INSERMCIMLMarseilleFrance
- Aix‐Marseille University, CNRS, INSERMCIML, Turing Center for Living SystemsMarseilleFrance
| | | | - Caroline Huber
- Aix Marseille University, CNRS, INSERMCIMLMarseilleFrance
| | | | - Roland P Bourette
- CNRS, INSERM, CHU Lille, University LilleUMR9020‐U1277 ‐ CANTHER – Cancer Heterogeneity Plasticity and Resistance to TherapiesLilleFrance
| | | | - Martin Bornhäuser
- Center for Regenerative Therapies Dresden (CRTD)Technical University DresdenDresdenGermany
- Department of Internal Medicine IUniversity Hospital Carl Gustav Carus DresdenDresdenGermany
- National Center for Tumor Diseases (NCT), DresdenDresdenGermany
| | - Sandrine Sarrazin
- Center for Regenerative Therapies Dresden (CRTD)Technical University DresdenDresdenGermany
- Aix Marseille University, CNRS, INSERMCIMLMarseilleFrance
| | - Marc Dalod
- Aix Marseille University, CNRS, INSERMCIMLMarseilleFrance
- Aix‐Marseille University, CNRS, INSERMCIML, Turing Center for Living SystemsMarseilleFrance
| | - Michael H Sieweke
- Center for Regenerative Therapies Dresden (CRTD)Technical University DresdenDresdenGermany
- Aix Marseille University, CNRS, INSERMCIMLMarseilleFrance
| |
Collapse
|
|
11
|
McKendrick JG, Jones GR, Elder SS, Watson E, T'Jonck W, Mercer E, Magalhaes MS, Rocchi C, Hegarty LM, Johnson AL, Schneider C, Becher B, Pridans C, Mabbott N, Liu Z, Ginhoux F, Bajenoff M, Gentek R, Bain CC, Emmerson E. CSF1R-dependent macrophages in the salivary gland are essential for epithelial regeneration after radiation-induced injury. Sci Immunol 2023; 8:eadd4374. [PMID: 37922341 DOI: 10.1126/sciimmunol.add4374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Accepted: 10/03/2023] [Indexed: 11/05/2023]
Abstract
The salivary glands often become damaged in individuals receiving radiotherapy for head and neck cancer, resulting in chronic dry mouth. This leads to detrimental effects on their health and quality of life, for which there is no regenerative therapy. Macrophages are the predominant immune cell in the salivary glands and are attractive therapeutic targets due to their unrivaled capacity to drive tissue repair. Yet, the nature and role of macrophages in salivary gland homeostasis and how they may contribute to tissue repair after injury are not well understood. Here, we show that at least two phenotypically and transcriptionally distinct CX3CR1+ macrophage populations are present in the adult salivary gland, which occupy anatomically distinct niches. CD11c+CD206-CD163- macrophages typically associate with gland epithelium, whereas CD11c-CD206+CD163+ macrophages associate with blood vessels and nerves. Using a suite of complementary fate mapping systems, we show that there are highly dynamic changes in the ontogeny and composition of salivary gland macrophages with age. Using an in vivo model of radiation-induced salivary gland injury combined with genetic or antibody-mediated depletion of macrophages, we demonstrate an essential role for macrophages in clearance of cells with DNA damage. Furthermore, we show that epithelial-associated macrophages are indispensable for effective tissue repair and gland function after radiation-induced injury, with their depletion resulting in reduced saliva production. Our data, therefore, provide a strong case for exploring the therapeutic potential of manipulating macrophages to promote tissue repair and thus minimize salivary gland dysfunction after radiotherapy.
Collapse
Affiliation(s)
- John G McKendrick
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, 4-5 Little France Drive, Edinburgh, EH16 4UU, UK
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, 4-5 Little France Drive, Edinburgh, EH16 4UU, UK
| | - Gareth-Rhys Jones
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, 4-5 Little France Drive, Edinburgh, EH16 4UU, UK
| | - Sonia S Elder
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, 4-5 Little France Drive, Edinburgh, EH16 4UU, UK
| | - Erin Watson
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, 4-5 Little France Drive, Edinburgh, EH16 4UU, UK
| | - Wouter T'Jonck
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, 4-5 Little France Drive, Edinburgh, EH16 4UU, UK
| | - Ella Mercer
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, 4-5 Little France Drive, Edinburgh, EH16 4UU, UK
| | - Marlene S Magalhaes
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, 4-5 Little France Drive, Edinburgh, EH16 4UU, UK
- Centre for Reproductive Health, Institute for Regeneration and Repair, University of Edinburgh, 4-5 Little France Drive, Edinburgh, EH16 4UU, UK
| | - Cecilia Rocchi
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, 4-5 Little France Drive, Edinburgh, EH16 4UU, UK
| | - Lizi M Hegarty
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, 4-5 Little France Drive, Edinburgh, EH16 4UU, UK
| | - Amanda L Johnson
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, 4-5 Little France Drive, Edinburgh, EH16 4UU, UK
| | | | - Burkhard Becher
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Clare Pridans
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, 4-5 Little France Drive, Edinburgh, EH16 4UU, UK
| | - Neil Mabbott
- Roslin Institute & Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush Campus, Midlothian EH25 9RG, UK
| | - Zhaoyuan Liu
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Florent Ginhoux
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore
- Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore, Singapore
| | - Marc Bajenoff
- Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université UM2, INSERM, U1104, CNRS UMR7280, Marseille 13288, France
| | - Rebecca Gentek
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, 4-5 Little France Drive, Edinburgh, EH16 4UU, UK
- Centre for Reproductive Health, Institute for Regeneration and Repair, University of Edinburgh, 4-5 Little France Drive, Edinburgh, EH16 4UU, UK
| | - Calum C Bain
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, 4-5 Little France Drive, Edinburgh, EH16 4UU, UK
| | - Elaine Emmerson
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, 4-5 Little France Drive, Edinburgh, EH16 4UU, UK
| |
Collapse
|
|
12
|
Tollemar V, Ström J, Tudzarovski N, Häbel H, Legert KG, Heymann R, Warfvinge G, Le Blanc K, Sugars RV. Immunohistopathology of oral mucosal chronic graft-versus-host disease severity and duration. Oral Dis 2023; 29:3346-3359. [PMID: 35796584 DOI: 10.1111/odi.14303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 06/23/2022] [Accepted: 07/04/2022] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Chronic graft-versus-host disease (cGVHD) is the main cause of late non-relapse mortality following hematopoietic cell transplantation. Oral mucosal (om-) cGVHD is common, but diagnosis and assessment rely on clinical interpretation and patient-reported symptoms. We investigated immunohistopathological profiles with respect to om-cGVHD severity disease duration. MATERIAL AND METHODS Ninety-four transplant patients and 15 healthy controls (n = 212 biopsies) were investigated by quantitative immunohistochemistry for T cells (CD4, CD8, and CD5), B cells (CD19 and CD20), macrophages (CD68), and Langerhans cells (CD1a). RESULTS We found significant increases in T (CD4, CD8) and monocytic (CD68) cells in om-cGVHD, and a notable absence of B (CD19 and CD20) cells. Histopathological activity correlated with increased CD4, CD8 and CD68. However, CD4 was associated with mild om-cGVHD, whereas CD8 and CD68 were found to be elevated in severe om-cGVHD. CD8 and CD68 levels were raised at disease onset, but during late phase, the predominant CD68 population was accompanied by CD4. CONCLUSION Oral cGVHD is a heterogenous clinical disorder, but our knowledge of the underlying biology remains limited. We highlight the importance of CD4, CD8 and CD68 immune profiling, together with histological grading for the staging of oral cGVHD, to broaden our understanding of the biology and individual disease course.
Collapse
Affiliation(s)
- Victor Tollemar
- Division of Oral Diagnostics and Rehabilitation, Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Jennifer Ström
- Division of Oral Diagnostics and Rehabilitation, Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Nikolce Tudzarovski
- Division of Oral Diagnostics and Rehabilitation, Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Henrike Häbel
- Division of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Karin Garming Legert
- Division of Oral Diagnostics and Rehabilitation, Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Robert Heymann
- Division of Oral Diagnostics and Rehabilitation, Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden
- Medical Unit for Reconstructive Plastic- and Craniofacial Surgery, Karolinska University Hospital, Stockholm, Sweden
| | - Gunnar Warfvinge
- Department of Oral Pathology, Faculty of Odontology, Malmö University, Malmö, Sweden
| | - Katarina Le Blanc
- Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
- Center of Allogeneic Stem Cell Transplantation and Cellular Therapy (CAST), Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Rachael Victoria Sugars
- Division of Oral Diagnostics and Rehabilitation, Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden
| |
Collapse
|
|
13
|
Rodríguez Mesa XM, Contreras Bolaños LA, Modesti Costa G, Mejia AL, Santander González SP. A Bidens pilosa L. Non-Polar Extract Modulates the Polarization of Human Macrophages and Dendritic Cells into an Anti-Inflammatory Phenotype. Molecules 2023; 28:7094. [PMID: 37894572 PMCID: PMC10608814 DOI: 10.3390/molecules28207094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 10/03/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
Different communities around the world traditionally use Bidens pilosa L. for medicinal purposes, mainly for its anti-inflammatory, antinociceptive, and antioxidant properties; it is used as an ingredient in teas or herbal medicines for the treatment of pain, inflammation, and immunological disorders. Several studies have been conducted that prove the immunomodulatory properties of this plant; however, it is not known whether the immunomodulatory properties of B. pilosa are mediated by its ability to modulate antigen-presenting cells (APCs) such as macrophages (MØs) and dendritic cells (DCs) (through polarization or the maturation state, respectively). Different polar and non-polar extracts and fractions were prepared from the aerial part of B. pilosa. Their cytotoxic and immunomodulatory effects were first tested on human peripheral blood mononuclear cells (PBMCs) and phytohemagglutinin (PHA)-stimulated PBMCs, respectively, via an MTT assay. Then, the non-cytotoxic plant extracts and fractions that showed the highest immunomodulatory activity were selected to evaluate their effects on human MØ polarization and DC maturation (cell surface phenotype and cytokine secretion) through multiparametric flow cytometry. Finally, the chemical compounds of the B. pilosa extract that showed the most significant immunomodulatory effects on human APCs were identified using gas chromatography coupled with mass spectrometry. The petroleum ether extract and the ethyl acetate and hydroalcoholic fractions obtained from B. pilosa showed low cytotoxicity and modulated the PHA-stimulated proliferation of PBMCs. Furthermore, the B. pilosa petroleum ether extract induced M2 polarization or a hybrid M1/M2 phenotype in MØs and a semi-mature status in DCs, regardless of exposure to a maturation stimulus. The immunomodulatory activity of the non-polar (petroleum ether) extract of B. pilosa on human PBMC proliferation, M2 polarization of MØs, and semi-mature status in DCs might be attributed to the low-medium polarity components in the extract, such as phytosterol terpenes and fatty acid esters.
Collapse
Affiliation(s)
| | | | - Geison Modesti Costa
- Phytochemistry Research Group (GIFUJ), Pontificia Universidad Javeriana, Bogotá 110231, Colombia
| | - Antonio Luis Mejia
- Phytoimmunomodulation Research Group, Juan N. Corpas University Foundation, Bogotá 111161, Colombia
| | | |
Collapse
|
|
14
|
Li X, Wu J, Zhu S, Wei Q, Wang L, Chen J. Intragraft immune cells: accomplices or antagonists of recipient-derived macrophages in allograft fibrosis? Cell Mol Life Sci 2023; 80:195. [PMID: 37395809 DOI: 10.1007/s00018-023-04846-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 05/22/2023] [Accepted: 06/21/2023] [Indexed: 07/04/2023]
Abstract
Organ fibrosis caused by chronic allograft rejection is a major concern in the field of transplantation. Macrophage-to-myofibroblast transition plays a critical role in chronic allograft fibrosis. Adaptive immune cells (such as B and CD4+ T cells) and innate immune cells (such as neutrophils and innate lymphoid cells) participate in the occurrence of recipient-derived macrophages transformed to myofibroblasts by secreting cytokines, which eventually leads to fibrosis of the transplanted organ. This review provides an update on the latest progress in understanding the plasticity of recipient-derived macrophages in chronic allograft rejection. We discuss here the immune mechanisms of allograft fibrosis and review the reaction of immune cells in allograft. The interactions between immune cells and the process of myofibroblast formulation are being considered for the potential therapeutic targets of chronic allograft fibrosis. Therefore, research on this topic seems to provide novel clues for developing strategies for preventing and treating allograft fibrosis.
Collapse
Affiliation(s)
- Xiaoping Li
- Cancer Center, First Hospital of Jilin University, Changchun, 130021, Jilin, China
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, 130061, Jilin, China
- Department of Pediatrics, First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Jing Wu
- Cancer Center, First Hospital of Jilin University, Changchun, 130021, Jilin, China
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, 130061, Jilin, China
| | - Shan Zhu
- Cancer Center, First Hospital of Jilin University, Changchun, 130021, Jilin, China
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, 130061, Jilin, China
| | - Qiuyu Wei
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, 130061, Jilin, China
| | - Liyan Wang
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, 130061, Jilin, China
| | - Jingtao Chen
- Cancer Center, First Hospital of Jilin University, Changchun, 130021, Jilin, China.
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, 130061, Jilin, China.
| |
Collapse
|
|
15
|
Tollemar V, Garming Legert K, Sugars RV. Perspectives on oral chronic graft-versus-host disease from immunobiology to morbid diagnoses. Front Immunol 2023; 14:1151493. [PMID: 37449200 PMCID: PMC10338056 DOI: 10.3389/fimmu.2023.1151493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 06/12/2023] [Indexed: 07/18/2023] Open
Abstract
Chronic Graft-versus-Host Disease (cGVHD) is a major long-term complication, associated with morbidity and mortality in patients following allogenic hematopoietic cell transplantation (HCT) for immune hematopoietic disorders. The mouth is one of the most frequently affected organs after HCT (45-83%) and oral cGVHD, which may appear as the first visible sign. Manifestations present with mucosal lichenoid lesions, salivary gland dysfunction and limited oral aperture. Diagnosis of oral cGVHD severity is based on mucosal lesions with symptoms of sensitivity and pain and reduced oral intake. However, diagnostic difficulties arise due to subjective definitions and low specificity to cover the spectrum of oral cGVHD. In recent years there have been significant improvements in our understanding of the underlying oral cGVHD disease mechanisms. Drawing upon the current knowledge on the pathophysiology and biological phases of oral cGVHD, we address oral mucosa lichenoid and Sjogren's Syndrome-like sicca syndromes. We consider the response of alloreactive T-cells and macrophages to recipient tissues to drive the pathophysiological reactions and biological phases of acute inflammation (phase 1), chronic inflammation and dysregulated immunity (phase 2), and subsequent aberrant fibrotic healing (phase 3), which in time may be associated with an increased malignant transformation rate. When formulating treatment strategies, the pathophysiological spectrum of cGVHD is patient dependent and not every patient may progress chronologically through the biological stages. As such there remains a need to address and clarify personalized diagnostics and management to improve treatment descriptions. Within this review, we highlight the current state of the art knowledge on oral cGVHD pathophysiology and biological phases. We address knowledge gaps of oral cGVHD, with a view to facilitate clinical management and improve research quality on lichenoid biology and morbid forms of oral cGVHD.
Collapse
Affiliation(s)
| | | | - Rachael V. Sugars
- Division of Oral Diagnostics and Rehabilitation, Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden
| |
Collapse
|
|
16
|
Ott LC, Cuenca AG. Innate immune cellular therapeutics in transplantation. FRONTIERS IN TRANSPLANTATION 2023; 2:1067512. [PMID: 37994308 PMCID: PMC10664839 DOI: 10.3389/frtra.2023.1067512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/24/2023]
Abstract
Successful organ transplantation provides an opportunity to extend the lives of patients with end-stage organ failure. Selectively suppressing the donor-specific alloimmune response, however, remains challenging without the continuous use of non-specific immunosuppressive medications, which have multiple adverse effects including elevated risks of infection, chronic kidney injury, cardiovascular disease, and cancer. Efforts to promote allograft tolerance have focused on manipulating the adaptive immune response, but long-term allograft survival rates remain disappointing. In recent years, the innate immune system has become an attractive therapeutic target for the prevention and treatment of transplant organ rejection. Indeed, contemporary studies demonstrate that innate immune cells participate in both the initial alloimmune response and chronic allograft rejection and undergo non-permanent functional reprogramming in a phenomenon termed "trained immunity." Several types of innate immune cells are currently under investigation as potential therapeutics in transplantation, including myeloid-derived suppressor cells, dendritic cells, regulatory macrophages, natural killer cells, and innate lymphoid cells. In this review, we discuss the features and functions of these cell types, with a focus on their role in the alloimmune response. We examine their potential application as therapeutics to prevent or treat allograft rejection, as well as challenges in their clinical translation and future directions for investigation.
Collapse
Affiliation(s)
- Leah C Ott
- Department of General Surgery, Boston Children's Hospital, Boston, MA, United States
| | - Alex G Cuenca
- Department of General Surgery, Boston Children's Hospital, Boston, MA, United States
| |
Collapse
|
|
17
|
Dander E, Vinci P, Vetrano S, Recordati C, Piazza R, Fazio G, Bardelli D, Bugatti M, Sozio F, Piontini A, Bonanomi S, Bertola L, Tassistro E, Valsecchi MG, Calza S, Vermi W, Biondi A, Del Prete A, Sozzani S, D'Amico G. The chemerin/CMKLR1 axis regulates intestinal graft-versus-host disease. JCI Insight 2023; 8:154440. [PMID: 36883565 PMCID: PMC10077469 DOI: 10.1172/jci.insight.154440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 01/23/2023] [Indexed: 03/09/2023] Open
Abstract
Gastrointestinal graft-versus-host disease (GvHD) is a major cause of mortality and morbidity following allogeneic bone marrow transplantation (allo-BMT). Chemerin is a chemotactic protein that recruits leukocytes to inflamed tissues by interacting with ChemR23/CMKLR1, a chemotactic receptor expressed by leukocytes, including macrophages. During acute GvHD, chemerin plasma levels were strongly increased in allo-BM-transplanted mice. The role of the chemerin/CMKLR1 axis in GvHD was investigated using Cmklr1-KO mice. WT mice transplanted with an allogeneic graft from Cmklr1-KO donors (t-KO) had worse survival and more severe GvHD. Histological analysis demonstrated that the gastrointestinal tract was the organ mostly affected by GvHD in t-KO mice. The severe colitis of t-KO mice was characterized by massive neutrophil infiltration and tissue damage associated with bacterial translocation and exacerbated inflammation. Similarly, Cmklr1-KO recipient mice showed increased intestinal pathology in both allogeneic transplant and dextran sulfate sodium-induced colitis. Notably, the adoptive transfer of WT monocytes into t-KO mice mitigated GvHD manifestations by decreasing gut inflammation and T cell activation. In patients, higher chemerin serum levels were predictive of GvHD development. Overall, these results suggest that CMKLR1/chemerin may be a protective pathway for the control of intestinal inflammation and tissue damage in GvHD.
Collapse
Affiliation(s)
- Erica Dander
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Paola Vinci
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Stefania Vetrano
- Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, Italy.,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Camilla Recordati
- Department of Veterinary Medicine, University of Milan, Lodi, Italy.,Mouse and Animal Pathology Laboratory, Fondazione Unimi, Milan, Italy
| | - Rocco Piazza
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,Hematology Division and Bone Marrow Unit, San Gerardo Hospital, Monza, Italy
| | - Grazia Fazio
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Donatella Bardelli
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Mattia Bugatti
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Francesca Sozio
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.,Humanitas Clinical and Research Center-IRCCS, Rozzano, Italy
| | - Andrea Piontini
- Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, Italy.,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Sonia Bonanomi
- Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Luca Bertola
- Department of Veterinary Medicine, University of Milan, Lodi, Italy.,Mouse and Animal Pathology Laboratory, Fondazione Unimi, Milan, Italy
| | - Elena Tassistro
- Bicocca Center of Bioinformatics, Biostatistics and Bioimaging (B4 center), School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Maria Grazia Valsecchi
- Bicocca Center of Bioinformatics, Biostatistics and Bioimaging (B4 center), School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Stefano Calza
- Biostatistics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - William Vermi
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Andrea Biondi
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.,Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.,School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Annalisa Del Prete
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.,Humanitas Clinical and Research Center-IRCCS, Rozzano, Italy
| | - Silvano Sozzani
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome, Italy.,IRCCS Neuromed, Pozzilli, Italy
| | - Giovanna D'Amico
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| |
Collapse
|
|
18
|
Lymph Node Fibroblastic Reticular Cells Attenuate Immune Responses Through Induction of Tolerogenic Macrophages at Early Stage of Transplantation. Transplantation 2023; 107:140-155. [PMID: 35876378 DOI: 10.1097/tp.0000000000004245] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Fibroblastic reticular cells (FRCs) are a type of stromal cells located in the T zone in secondary lymphoid organs. Previous studies showed that FRCs possess the potential to promote myeloid differentiation. We aim to investigate whether FRCs in lymph nodes (LNs) could induce tolerogenic macrophage generation and further influence T-cell immunity at an early stage of allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS LNs were assayed to confirm the existence of proliferating macrophages after allo-HSCT. Ex vivo-expanded FRCs and bone marrow cells were cocultured to verify the generation of macrophages. Real-time quantitative PCR and ELISA assays were performed to observe the cytokines expressed by FRC. Transcriptome sequencing was performed to compare the difference between FRC-induced macrophages (FMs) and conventional macrophages. Mixed lymphocyte reaction and the utilization of FMs in acute graft-versus-host disease (aGVHD) mice were used to test the inhibitory function of FMs in T-cell immunity in vitro and in vivo. RESULTS We found a large number of proliferating macrophages near FRCs in LNs with tolerogenic phenotype under allo-HSCT conditions. Neutralizing anti-macrophage colony-stimulating factor receptor antibody abolished FMs generation in vitro. Phenotypic analysis and transcriptome sequencing suggested FMs possessed immunoinhibitory function. Mixed lymphocyte reaction proved that FMs could inhibit T-cell activation and differentiation toward Th1/Tc1 cells. Injection of FMs in aGVHD mice effectively attenuated aGVHD severity and mortality. CONCLUSIONS This study has revealed a novel mechanism of immune regulation through the generation of FRC-induced tolerogenic macrophages in LNs at an early stage of allo-HSCT.
Collapse
|
|
19
|
Hong C, Lu H, Huang X, Chen M, Jin R, Dai X, Gong F, Dong H, Wang H, Gao XM. Neutrophils as regulators of macrophage-induced inflammation in a setting of allogeneic bone marrow transplantation. Stem Cell Reports 2022; 17:1561-1575. [PMID: 35777356 PMCID: PMC9287675 DOI: 10.1016/j.stemcr.2022.05.021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 05/30/2022] [Accepted: 05/31/2022] [Indexed: 11/26/2022] Open
Abstract
Clinical data reveal that patients with allogeneic hematopoietic stem cell transplantation (HSCT) are vulnerable to infection and prone to developing severe sepsis, which greatly compromises the success of transplantation, indicating a dysregulation of inflammatory immune response in this clinical setting. Here, by using a mouse model of haploidentical bone marrow transplantation (haplo-BMT), we found that uncontrolled macrophage inflammation underlies the pathogenesis of both LPS- and E.coli-induced sepsis in recipient animals with graft-versus-host disease (GVHD). Deficient neutrophil maturation in GVHD mice post-haplo-BMT diminished modulation of macrophage-induced inflammation, which was mechanistically dependent on MMP9-mediated activation of TGF-β1. Accordingly, adoptive transfer of mature neutrophils purified from wild-type donor mice inhibited both sterile and infectious sepsis in GVHD mice post-haplo-BMT. Together, our findings identify a novel mature neutrophil-dependent regulation of macrophage inflammatory response in a haplo-BMT setting and provide useful clues for developing clinical strategies for patients suffering from post-HSCT sepsis.
Macrophage inflammation leads to the development of post-haplo-BMT sepsis Impaired neutrophil maturation diminishes regulation of macrophage inflammation Extramedullary granulopoiesis fails to support neutrophil maturation after haplo-BMT Neutrophils regulate macrophage inflammation via MMP9-mediated TGF-β1 activation
Collapse
Affiliation(s)
- Chao Hong
- Institutes of Biology and Medical Sciences, Soochow University, 199 Ren-Ai Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China.
| | - Hongyun Lu
- Institutes of Biology and Medical Sciences, Soochow University, 199 Ren-Ai Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
| | - Xiaohong Huang
- Institutes of Biology and Medical Sciences, Soochow University, 199 Ren-Ai Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
| | - Ming Chen
- Institutes of Biology and Medical Sciences, Soochow University, 199 Ren-Ai Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
| | - Rong Jin
- Institutes of Biology and Medical Sciences, Soochow University, 199 Ren-Ai Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
| | - Xiaoqiu Dai
- Institutes of Biology and Medical Sciences, Soochow University, 199 Ren-Ai Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
| | - Fangyuan Gong
- Institutes of Biology and Medical Sciences, Soochow University, 199 Ren-Ai Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
| | - Hongliang Dong
- Institutes of Biology and Medical Sciences, Soochow University, 199 Ren-Ai Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
| | - Hongmin Wang
- Institutes of Biology and Medical Sciences, Soochow University, 199 Ren-Ai Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
| | - Xiao-Ming Gao
- Institutes of Biology and Medical Sciences, Soochow University, 199 Ren-Ai Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China.
| |
Collapse
|
|
20
|
Colony stimulating factor-1 producing endothelial cells and mesenchymal stromal cells maintain monocytes within a perivascular bone marrow niche. Immunity 2022; 55:862-878.e8. [PMID: 35508166 DOI: 10.1016/j.immuni.2022.04.005] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 01/13/2022] [Accepted: 04/08/2022] [Indexed: 12/15/2022]
Abstract
Macrophage colony stimulating factor-1 (CSF-1) plays a critical role in maintaining myeloid lineage cells. However, congenital global deficiency of CSF-1 (Csf1op/op) causes severe musculoskeletal defects that may indirectly affect hematopoiesis. Indeed, we show here that osteolineage-derived Csf1 prevented developmental abnormalities but had no effect on monopoiesis in adulthood. However, ubiquitous deletion of Csf1 conditionally in adulthood decreased monocyte survival, differentiation, and migration, independent of its effects on bone development. Bone histology revealed that monocytes reside near sinusoidal endothelial cells (ECs) and leptin receptor (Lepr)-expressing perivascular mesenchymal stromal cells (MSCs). Targeted deletion of Csf1 from sinusoidal ECs selectively reduced Ly6C- monocytes, whereas combined depletion of Csf1 from ECs and MSCs further decreased Ly6Chi cells. Moreover, EC-derived CSF-1 facilitated recovery of Ly6C- monocytes and protected mice from weight loss following induction of polymicrobial sepsis. Thus, monocytes are supported by distinct cellular sources of CSF-1 within a perivascular BM niche.
Collapse
|
|
21
|
Tumor-Associated Macrophages in Gliomas—Basic Insights and Treatment Opportunities. Cancers (Basel) 2022; 14:cancers14051319. [PMID: 35267626 PMCID: PMC8909866 DOI: 10.3390/cancers14051319] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 02/22/2022] [Accepted: 02/25/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Macrophages are a specialized immune cell type found in both invertebrates and vertebrates. Versatile in functionality, macrophages carry out important tasks such as cleaning cellular debris in healthy tissues and mounting immune responses during infection. In many cancer types, macrophages make up a significant portion of tumor tissue, and these are aptly called tumor-associated macrophages. In gliomas, a group of primary brain tumors, these macrophages are found in very high frequency. Tumor-associated macrophages can promote glioma development and influence the outcome of various therapeutic regimens. At the same time, these cells provide various potential points of intervention for therapeutic approaches in glioma patients. The significance of tumor-associated macrophages in the glioma microenvironment and potential therapeutic targets are the focus of this review. Abstract Glioma refers to a group of primary brain tumors which includes glioblastoma (GBM), astrocytoma and oligodendroglioma as major entities. Among these, GBM is the most frequent and most malignant one. The highly infiltrative nature of gliomas, and their intrinsic intra- and intertumoral heterogeneity, pose challenges towards developing effective treatments. The glioma microenvironment, in addition, is also thought to play a critical role during tumor development and treatment course. Unlike most other solid tumors, the glioma microenvironment is dominated by macrophages and microglia—collectively known as tumor-associated macrophages (TAMs). TAMs, like their homeostatic counterparts, are plastic in nature and can polarize to either pro-inflammatory or immunosuppressive states. Many lines of evidence suggest that immunosuppressive TAMs dominate the glioma microenvironment, which fosters tumor development, contributes to tumor aggressiveness and recurrence and, very importantly, impedes the therapeutic effect of various treatment regimens. However, through the development of new therapeutic strategies, TAMs can potentially be shifted towards a proinflammatory state which is of great therapeutic interest. In this review, we will discuss various aspects of TAMs in the context of glioma. The focus will be on the basic biology of TAMs in the central nervous system (CNS), potential biomarkers, critical evaluation of model systems for studying TAMs and finally, special attention will be given to the potential targeted therapeutic options that involve the TAM compartment in gliomas.
Collapse
|
|
22
|
AT A, T GD, HM R, ES B, FL J. Calprotectin expressing donor-derived macrophages increase in acute gastrointestinal graft versus host disease. Transplant Cell Ther 2022; 28:248.e1-248.e8. [DOI: 10.1016/j.jtct.2022.01.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 01/18/2022] [Accepted: 01/28/2022] [Indexed: 10/19/2022]
|
|
23
|
Michniacki TF, Choi SW, Peltier DC. Immune Suppression in Allogeneic Hematopoietic Stem Cell Transplantation. Handb Exp Pharmacol 2022; 272:209-243. [PMID: 34628553 PMCID: PMC9055779 DOI: 10.1007/164_2021_544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for high-risk hematologic disorders. There are multiple immune-mediated complications following allo-HSCT that are prevented and/or treated by immunosuppressive agents. Principal among these immune-mediated complications is acute graft-versus-host disease (aGVHD), which occurs when the new donor immune system targets host tissue antigens. The immunobiology of aGVHD is complex and involves all aspects of the immune system. Due to the risk of aGVHD, immunosuppressive aGVHD prophylaxis is required for nearly all allogeneic HSCT recipients. Despite prophylaxis, aGVHD remains a major cause of nonrelapse mortality. Here, we discuss the clinical features of aGVHD, the immunobiology of aGVHD, the immunosuppressive therapies used to prevent and treat aGVHD, how to mitigate the side effects of these immunosuppressive therapies, and what additional immune-mediated post-allo-HSCT complications are also treated with immunosuppression.
Collapse
Affiliation(s)
- Thomas F Michniacki
- Division of Hematology/Oncology, Department of Pediatrics, Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA
| | - Sung Won Choi
- Division of Hematology/Oncology, Department of Pediatrics, Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA.
- University of Michigan Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
| | - Daniel C Peltier
- Division of Hematology/Oncology, Department of Pediatrics, Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA.
- University of Michigan Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
| |
Collapse
|
|
24
|
Martin PJ, Storer BE, Levine DM, Hansen JA. Genetic variants associated with inflammatory bowel disease and gut graft-versus-host disease. Blood Adv 2021; 5:4456-4464. [PMID: 34535014 PMCID: PMC8579259 DOI: 10.1182/bloodadvances.2021004959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 07/03/2021] [Indexed: 11/29/2022] Open
Abstract
Previous studies have identified genetic variants associated with inflammatory bowel disease (IBD). We tested the hypothesis that some of these variants are also associated with the risk of moderate to severe gut graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). Associations were evaluated initially in a discovery cohort of 1980 HCT recipients of European ancestry with HLA-matched related or unrelated donors. Associations discovered in this cohort were tested for replication in a separate cohort of 1294 HCT recipients. Among the 296 single-nucleotide polymorphisms and 26 HLA alleles tested, we found that the recipient rs1260326 homozygous T allele in GCKR was associated with a higher risk of stage 2 to 4 gut GVHD. No other candidate variants were associated with stage 2 to 4 gut GVHD. The rs1260326 variant resides in an IBD-associated locus containing FNDC4, a gene that encodes a secreted anti-inflammatory factor that dampens macrophage activity and improves colitis in mice. Our results suggest that targeting inflammatory macrophages with recombinant FNDC4 offers an attractive avenue of clinical investigation for management of IBD and gut GVHD.
Collapse
Affiliation(s)
- Paul J. Martin
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
- Department of Medicine, University of Washington School of Medicine, Seattle, WA; and
| | - Barry E. Storer
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - David M. Levine
- Department of Biostatistics, University of Washington, Seattle, WA
| | - John A. Hansen
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
- Department of Medicine, University of Washington School of Medicine, Seattle, WA; and
| |
Collapse
|
|
25
|
Sehgal A, Irvine KM, Hume DA. Functions of macrophage colony-stimulating factor (CSF1) in development, homeostasis, and tissue repair. Semin Immunol 2021; 54:101509. [PMID: 34742624 DOI: 10.1016/j.smim.2021.101509] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 10/23/2021] [Indexed: 12/16/2022]
Abstract
Macrophage colony-stimulating factor (CSF1) is the primary growth factor required for the control of monocyte and macrophage differentiation, survival, proliferation and renewal. Although the cDNAs encoding multiple isoforms of human CSF1 were cloned in the 1980s, and recombinant proteins were available for testing in humans, CSF1 has not yet found substantial clinical application. Here we present an overview of CSF1 biology, including evolution, regulation and functions of cell surface and secreted isoforms. CSF1 is widely-expressed, primarily by cells of mesenchymal lineages, in all mouse tissues. Cell-specific deletion of a floxed Csf1 allele in mice indicates that local CSF1 production contributes to the maintenance of tissue-specific macrophage populations but is not saturating. CSF1 in the circulation is controlled primarily by receptor-mediated clearance by macrophages in liver and spleen. Administration of recombinant CSF1 to humans or animals leads to monocytosis and expansion of tissue macrophage populations and growth of the liver and spleen. In a wide variety of tissue injury models, CSF1 administration promotes monocyte infiltration, clearance of damaged cells and repair. We suggest that CSF1 has therapeutic potential in regenerative medicine.
Collapse
Affiliation(s)
- Anuj Sehgal
- Mater Research Institute-University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
| | - Katharine M Irvine
- Mater Research Institute-University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
| | - David A Hume
- Mater Research Institute-University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
| |
Collapse
|
|
26
|
Ara T, Hashimoto D. Novel Insights Into the Mechanism of GVHD-Induced Tissue Damage. Front Immunol 2021; 12:713631. [PMID: 34512636 PMCID: PMC8429834 DOI: 10.3389/fimmu.2021.713631] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Accepted: 08/10/2021] [Indexed: 12/22/2022] Open
Abstract
Prophylaxis for and treatment of graft-versus-host disease (GVHD) are essential for successful allogeneic hematopoietic stem cell transplantation (allo-SCT) and mainly consist of immunosuppressants such as calcineurin inhibitors. However, profound immunosuppression can lead to tumor relapse and infectious complications, which emphasizes the necessity of developing novel management strategies for GVHD. Emerging evidence has revealed that tissue-specific mechanisms maintaining tissue homeostasis and promoting tissue tolerance to combat GVHD are damaged after allo-SCT, resulting in exacerbation and treatment refractoriness of GVHD. In the gastrointestinal tract, epithelial regeneration derived from intestinal stem cells (ISCs), a microenvironment that maintains healthy gut microbiota, and physical and chemical mucosal barrier functions against pathogens are damaged by conditioning regimens and/or GVHD. The administration of growth factors for cells that maintain intestinal homeostasis, such as interleukin-22 (IL-22) for ISCs, R-spondin 1 (R-Spo1) for ISCs and Paneth cells, and interleukin-25 (IL-25) for goblet cells, mitigates murine GVHD. In this review, we summarize recent advances in the understanding of GVHD-induced tissue damage and emerging strategies for the management of GVHD.
Collapse
Affiliation(s)
- Takahide Ara
- Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Daigo Hashimoto
- Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan
| |
Collapse
|
|
27
|
Jeljeli M, Chêne C, Chouzenoux S, Thomas M, Segain B, Doridot L, Nicco C, Batteux F. LPS low-Macrophages Alleviate the Outcome of Graft- Versus-Host Disease Without Aggravating Lymphoma Growth in Mice. Front Immunol 2021; 12:670776. [PMID: 34413847 PMCID: PMC8369416 DOI: 10.3389/fimmu.2021.670776] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 07/07/2021] [Indexed: 02/06/2023] Open
Abstract
Despite significant therapeutic advances, graft-versus-host disease (GvHD) remains the main life-threatening complication following allogeneic hematopoietic stem cell transplantation. The pathogenesis of GvHD is dominated by a dysregulated allogeneic immune response that drives fibrosis and autoimmunity in chronic forms. A multitude of cell therapy approaches, including infusion of myeloid cells, has been proposed to prevent GvHD through tolerance induction but yielded variable results. Myeloid cells like macrophages can be reprogrammed to develop adaptive-like features following antigenic challenge to reinforce or inhibit a subsequent immune response; a phenomenon termed ‘trained immunity’. Here we report that, whereas LPSlow-trained macrophages elicit a suppressor effect on allogeneic T cell proliferation and function in vitro in an IL-10-dependent manner, Bacille Calmette et Guérin (BCG)-trained macrophages exert an opposite effect. In a murine model of sclerodermatous chronic GvHD, LPSlow-trained macrophages attenuate clinical signs of GvHD with significant effects on T cell phenotype and function, autoantibodies production, and tissue fibrosis. Furthermore, infusion of LPSlow-macrophages significantly improves survival in mice with acute GvHD. Importantly, we also provide evidence that LPSlow-macrophages do not accelerate A20-lymphoma tumor growth, which is significantly reduced upon transfer of BCG-macrophages. Collectively, these data indicate that macrophages can be trained to significantly inhibit in vitro and in vivo allo-reactive T cell proliferation without exhibiting pro-tumoral effect, thereby opening the way to promising clinical applications.
Collapse
Affiliation(s)
- Mohamed Jeljeli
- Département 3I «Infection, Immunité et Inflammation», Institut Cochin, INSERM U1016, Université de Paris, Paris, France.,Université de Paris, Faculté de Médecine, AP-HP-Centre Université de Paris, Hôpital Cochin, Service d'immunologie biologique, Paris, France
| | - Charlotte Chêne
- Département 3I «Infection, Immunité et Inflammation», Institut Cochin, INSERM U1016, Université de Paris, Paris, France
| | - Sandrine Chouzenoux
- Département 3I «Infection, Immunité et Inflammation», Institut Cochin, INSERM U1016, Université de Paris, Paris, France
| | - Marine Thomas
- Département 3I «Infection, Immunité et Inflammation», Institut Cochin, INSERM U1016, Université de Paris, Paris, France
| | - Benjamin Segain
- Département 3I «Infection, Immunité et Inflammation», Institut Cochin, INSERM U1016, Université de Paris, Paris, France
| | - Ludivine Doridot
- Département 3I «Infection, Immunité et Inflammation», Institut Cochin, INSERM U1016, Université de Paris, Paris, France
| | - Carole Nicco
- Département 3I «Infection, Immunité et Inflammation», Institut Cochin, INSERM U1016, Université de Paris, Paris, France
| | - Frédéric Batteux
- Département 3I «Infection, Immunité et Inflammation», Institut Cochin, INSERM U1016, Université de Paris, Paris, France.,Université de Paris, Faculté de Médecine, AP-HP-Centre Université de Paris, Hôpital Cochin, Service d'immunologie biologique, Paris, France
| |
Collapse
|
|
28
|
Hanaki R, Toyoda H, Iwamoto S, Morimoto M, Nakato D, Ito T, Niwa K, Amano K, Hashizume R, Tawara I, Hirayama M. Donor-derived M2 macrophages attenuate GVHD after allogeneic hematopoietic stem cell transplantation. IMMUNITY INFLAMMATION AND DISEASE 2021; 9:1489-1499. [PMID: 34410039 PMCID: PMC8589365 DOI: 10.1002/iid3.503] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 07/25/2021] [Accepted: 07/28/2021] [Indexed: 12/28/2022]
Abstract
Introduction Graft‐versus‐host disease (GVHD) is frequent and fatal complication following allogeneic hematopoietic stem cell transplantation (HSCT) and characteristically involves skin, gut, and liver. Macrophages promote tissue regeneration and mediate immunomodulation. Macrophages are divided into two different phenotypes, classically activated M1 (pro‐inflammatory or immune‐reactive macrophages) and alternatively activated M2 (anti‐inflammatory or immune‐suppressive macrophages). The anti‐inflammatory effect of M2 macrophage led us to test its effect in the pathophysiology of GVHD. Methods GVHD was induced in lethally irradiated BALB/c mice. M2 macrophages derived from donor bone marrow (BM) were administered intravenously, while controls received donor BM‐mononuclear cells and splenocytes. Animals were monitored for clinical GVHD and analyzed. Results We confirmed that administering donor BM‐derived M2 macrophages attenuated GVHD severity and prolonged survival after HSCT. Moreover, donor BM‐derived M2 macrophages significantly suppressed donor T cell proliferation by cell‐to‐cell contact in vitro. Conclusions We showed the protective effects of donor‐derived M2 macrophages on GVHD and improved survival in a model of HSCT. Our data suggest that donor‐derived M2 macrophages offer the potential for cell‐based therapy to treat GVHD.
Collapse
Affiliation(s)
- Ryo Hanaki
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Hidemi Toyoda
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Shotaro Iwamoto
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Mari Morimoto
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Daisuke Nakato
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Takahiro Ito
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Kaori Niwa
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Keishiro Amano
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Ryotaro Hashizume
- Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Isao Tawara
- Department of Hematology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Masahiro Hirayama
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| |
Collapse
|
|
29
|
Graft-versus-host disease: a disorder of tissue regeneration and repair. Blood 2021; 138:1657-1665. [PMID: 34370823 DOI: 10.1182/blood.2021011867] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 07/27/2021] [Indexed: 11/20/2022] Open
Abstract
Regenerative failure at barrier surfaces and maladaptive repair leading to fibrosis are hallmarks of graft-versus-host disease (GVHD). Although immunosuppressive treatment can control inflammation, impaired tissue homeostasis leads to prolonged organ damage and impaired quality of life. In this Spotlight article, we review recent research that addresses the critical failures in tissue regeneration and repair that underpin treatment-resistant GVHD. We highlight current interventions designed to overcome these defects and provide our assessment of the future therapeutic landscape.
Collapse
|
|
30
|
Vasamsetti SB, Coppin E, Zhang X, Florentin J, Koul S, Götberg M, Clugston AS, Thoma F, Sembrat J, Bullock GC, Kostka D, St Croix CM, Chattopadhyay A, Rojas M, Mulukutla SR, Dutta P. Apoptosis of hematopoietic progenitor-derived adipose tissue-resident macrophages contributes to insulin resistance after myocardial infarction. Sci Transl Med 2021; 12:12/553/eaaw0638. [PMID: 32718989 DOI: 10.1126/scitranslmed.aaw0638] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 11/27/2019] [Accepted: 07/01/2020] [Indexed: 12/13/2022]
Abstract
Patients with insulin resistance have high risk of cardiovascular disease such as myocardial infarction (MI). However, it is not known whether MI can initiate or aggravate insulin resistance. We observed that patients with ST-elevation MI and mice with MI had de novo hyperglycemia and features of insulin resistance, respectively. In mouse models of both myocardial and skeletal muscle injury, we observed that the number of visceral adipose tissue (VAT)-resident macrophages decreased because of apoptosis after these distant organ injuries. Patients displayed a similar decrease in VAT-resident macrophage numbers and developed systemic insulin resistance after ST-elevation MI. Loss of VAT-resident macrophages after MI injury led to systemic insulin resistance in non-diabetic mice. Danger signaling-associated protein high mobility group box 1 was released by the dead myocardium after MI in rodents and triggered macrophage apoptosis via Toll-like receptor 4. The VAT-resident macrophage population in the steady state in mice was transcriptomically distinct from macrophages in the brain, skin, kidney, bone marrow, lungs, and liver and was derived from hematopoietic progenitor cells just after birth. Mechanistically, VAT-resident macrophage apoptosis and de novo insulin resistance in mouse models of MI were linked to diminished concentrations of macrophage colony-stimulating factor and adiponectin. Collectively, these findings demonstrate a previously unappreciated role of adipose tissue-resident macrophages in sensing remote organ injury and promoting MI pathogenesis.
Collapse
Affiliation(s)
- Sathish Babu Vasamsetti
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Emilie Coppin
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.,Regeneration in Hematopoiesis, Leibniz Institute on Aging- Fritz Lipmann Institute, Jena 07745, Germany
| | - Xinyi Zhang
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.,The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Jonathan Florentin
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Sasha Koul
- Department of Cardiology, Lund University, Skane University Hospital, Lund, 22184, Sweden
| | - Matthias Götberg
- Department of Cardiology, Lund University, Skane University Hospital, Lund, 22184, Sweden
| | - Andrew S Clugston
- Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Floyd Thoma
- Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - John Sembrat
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.,Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
| | - Grant C Bullock
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Dennis Kostka
- Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | | | | | - Mauricio Rojas
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.,Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
| | - Suresh R Mulukutla
- Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Partha Dutta
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA. .,Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.,Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| |
Collapse
|
|
31
|
Tumor-associated myeloid cells provide critical support for T-ALL. Blood 2021; 136:1837-1850. [PMID: 32845007 DOI: 10.1182/blood.2020007145] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 06/26/2020] [Indexed: 12/13/2022] Open
Abstract
Despite harboring mutations in oncogenes and tumor suppressors that promote cancer growth, T-cell acute lymphoblastic leukemia (T-ALL) cells require exogenous cells or signals to survive in culture. We previously reported that myeloid cells, particularly dendritic cells, from the thymic tumor microenvironment support the survival and proliferation of primary mouse T-ALL cells in vitro. Thus, we hypothesized that tumor-associated myeloid cells would support T-ALL in vivo. Consistent with this possibility, in vivo depletion of myeloid cells results in a significant reduction in leukemia burden in multiple organs in 2 distinct mouse models of T-ALL and prolongs survival. The impact of the myeloid compartment on T-ALL growth is not dependent on suppression of antitumor T-cell responses. Instead, myeloid cells provide signals that directly support T-ALL cells. Transcriptional profiling, functional assays, and acute in vivo myeloid-depletion experiments identify activation of IGF1R as a critical component of myeloid-mediated T-ALL growth and survival. We identify several myeloid subsets that have the capacity to directly support survival of T-ALL cells. Consistent with mouse models, myeloid cells derived from human peripheral blood monocytes activate IGF1R and directly support survival of primary patient T-ALL cells in vitro. Furthermore, enriched macrophage gene signatures in published clinical samples correlate with inferior outcomes for pediatric T-ALL patients. Collectively, these data reveal that tumor-associated myeloid cells provide signals critical for T-ALL growth in multiple organs in vivo and implicate tumor-associated myeloid cells and associated signals as potential therapeutic targets.
Collapse
|
|
32
|
Macrophages and Stem Cells-Two to Tango for Tissue Repair? Biomolecules 2021; 11:biom11050697. [PMID: 34066618 PMCID: PMC8148606 DOI: 10.3390/biom11050697] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 04/26/2021] [Accepted: 05/04/2021] [Indexed: 12/25/2022] Open
Abstract
Macrophages (MCs) are present in all tissues, not only supporting homeostasis, but also playing an important role in organogenesis, post-injury regeneration, and diseases. They are a heterogeneous cell population due to their origin, tissue specificity, and polarization in response to aggression factors, depending on environmental cues. Thus, as pro-inflammatory M1 phagocytic MCs, they contribute to tissue damage and even fibrosis, but the anti-inflammatory M2 phenotype participates in repairing processes and wound healing through a molecular interplay with most cells in adult stem cell niches. In this review, we emphasize MC phenotypic heterogeneity in health and disease, highlighting their systemic and systematic contribution to tissue homeostasis and repair. Unraveling the intervention of both resident and migrated MCs on the behavior of stem cells and the regulation of the stem cell niche is crucial for opening new perspectives for novel therapeutic strategies in different diseases.
Collapse
|
|
33
|
Hill GR, Betts BC, Tkachev V, Kean LS, Blazar BR. Current Concepts and Advances in Graft-Versus-Host Disease Immunology. Annu Rev Immunol 2021; 39:19-49. [PMID: 33428454 PMCID: PMC8085043 DOI: 10.1146/annurev-immunol-102119-073227] [Citation(s) in RCA: 107] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Worldwide, each year over 30,000 patients undergo an allogeneic hema-topoietic stem cell transplantation with the intent to cure high-risk hematologic malignancy, immunodeficiency, metabolic disease, or a life-threatening bone marrow failure syndrome. Despite substantial advances in donor selection and conditioning regimens and greater availability of allograft sources, transplant recipients still endure the morbidity and mortality of graft-versus-host disease (GVHD). Herein, we identify key aspects of acute and chronic GVHD pathophysiology, including host/donor cell effectors, gut dysbiosis, immune system and cytokine imbalance, and the interface between inflammation and tissue fibrosis. In particular, we also summarize the translational application of this heightened understanding of immune dysregulation in the design of novel therapies to prevent and treat GVHD.
Collapse
Affiliation(s)
- Geoffrey R Hill
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;
- Division of Medical Oncology University of Washington, Seattle, Washington 98109, USA
| | - Brian C Betts
- Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA
| | - Victor Tkachev
- Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; ,
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Leslie S Kean
- Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; ,
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Bruce R Blazar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota 55455, USA;
| |
Collapse
|
|
34
|
CD169 + lymph node macrophages have protective functions in mouse breast cancer metastasis. Cell Rep 2021; 35:108993. [PMID: 33852863 DOI: 10.1016/j.celrep.2021.108993] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 11/01/2020] [Accepted: 03/24/2021] [Indexed: 12/12/2022] Open
Abstract
Although the contribution of macrophages to metastasis is widely studied in primary tumors, the involvement of macrophages in tumor-draining lymph nodes (LNs) in this process is less clear. We find CD169+ macrophages as the predominant macrophage subtype in naive LNs, which undergo proliferative expansion in response to tumor stimuli. CD169+ LN macrophage depletion, using an anti-CSF-1R antibody or clodronate-loaded liposomes, leads to increased metastatic burden in two mouse breast cancer models. The expansion of CD169+ macrophages is tightly connected to B cell expansion in tumor-draining LNs, and B cell depletion abrogates the effect of CD169+ macrophage absence on metastasis, indicating that the CD169+ macrophage anti-metastatic effects require B cell presence. These results reveal a protective role of CD169+ LN macrophages in breast cancer metastasis and raise caution for the use of drugs aiming at the depletion of tumor-associated macrophages, which might simultaneously deplete macrophages in tumor-draining LNs.
Collapse
|
|
35
|
Saw JL, Sidiqi MH, Mauermann ML, Alkhateeb H, Naddaf E. Immune-mediated neuromuscular complications of graft-versus-host disease. Muscle Nerve 2021; 63:852-860. [PMID: 33651380 DOI: 10.1002/mus.27214] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 02/20/2021] [Accepted: 02/27/2021] [Indexed: 12/11/2022]
Abstract
INTRODUCTION/AIMS We aimed to describe the clinical phenotype, histopathological findings and overall survival (OS) of the immune-mediated neuromuscular complications of graft-versus-host disease (GVHD). METHODS We conducted a retrospective chart review of adult patients presenting with immune-mediated neuromuscular complications of GVHD to Mayo Clinic, between April 2013 and July 2018.We collected clinical and laboratory characteristics, histopathological findings, response to treatment and survival data. RESULTS We identified 20 patients with a mean age at presentation of 55 y. Mean time from transplant to neurological presentation was 14 mo. Myositis was the most common complication seen in 17 patients, manifesting with predominantly axial and/or proximal weakness. Eleven patients had a muscle biopsy showing diffuse perimysial, predominantly macrophagic infiltration in 10, 3 of them with perimysial perivascular lymphocytic collections, and endomysial and perimysial lymphocytic infiltration in 1. Only two patients had a neuropathic complication: one each with acute inflammatory demyelinating polyradiculoneuropathy and neuralgic amyotrophy. A single patient had a myasthenic syndrome presenting with fluctuating foot drop. Nineteen patients were treated and all responded to immunosuppressive agents; however, 11 had further GVHD flares requiring escalation of therapy. After a median follow-up of 83 mo, seven (35%) patients died: five from progressive GVHD and two from infections. The 5-y OS from time of transplant was 68%. DISCUSSION Myositis is the most common immune-mediated neuromuscular complication of GVHD while peripheral neuropathy and myasthenic syndromes appear less common. The macrophage-predominant infiltration on muscle biopsy deserves further study to better clarify the role of macrophages in GVHD pathogenesis.
Collapse
Affiliation(s)
- Jacqui-Lyn Saw
- Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA
| | - M Hasib Sidiqi
- Department of Hematology, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Hassan Alkhateeb
- Department of Hematology, Mayo Clinic, Rochester, Minnesota, USA
| | - Elie Naddaf
- Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA
| |
Collapse
|
|
36
|
STING negatively regulates allogeneic T-cell responses by constraining antigen-presenting cell function. Cell Mol Immunol 2021; 18:632-643. [PMID: 33500563 PMCID: PMC8027033 DOI: 10.1038/s41423-020-00611-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 11/26/2020] [Indexed: 01/30/2023] Open
Abstract
Stimulator of interferon genes (STING)-mediated innate immune activation plays a key role in tumor- and self-DNA-elicited antitumor immunity and autoimmunity. However, STING can also suppress tumor immunity and autoimmunity. STING signaling in host nonhematopoietic cells was reported to either protect against or promote graft-versus-host disease (GVHD), a major complication of allogeneic hematopoietic cell transplantation (allo-HCT). Host hematopoietic antigen-presenting cells (APCs) play key roles in donor T-cell priming during GVHD initiation. However, how STING regulates host hematopoietic APCs after allo-HCT remains unknown. We utilized murine models of allo-HCT to assess the role of STING in hematopoietic APCs. STING-deficient recipients developed more severe GVHD after major histocompatibility complex-mismatched allo-HCT. Using bone marrow chimeras, we found that STING deficiency in host hematopoietic cells was primarily responsible for exacerbating the disease. Furthermore, STING on host CD11c+ cells played a dominant role in suppressing allogeneic T-cell responses. Mechanistically, STING deficiency resulted in increased survival, activation, and function of APCs, including macrophages and dendritic cells. Consistently, constitutive activation of STING attenuated the survival, activation, and function of APCs isolated from STING V154M knock-in mice. STING-deficient APCs augmented donor T-cell expansion, chemokine receptor expression, and migration into intestinal tissues, resulting in accelerated/exacerbated GVHD. Using pharmacologic approaches, we demonstrated that systemic administration of a STING agonist (bis-(3'-5')-cyclic dimeric guanosine monophosphate) to recipient mice before transplantation significantly reduced GVHD mortality. In conclusion, we revealed a novel role of STING in APC activity that dictates T-cell allogeneic responses and validated STING as a potential therapeutic target for controlling GVHD after allo-HCT.
Collapse
|
|
37
|
Freuchet A, Salama A, Remy S, Guillonneau C, Anegon I. IL-34 and CSF-1, deciphering similarities and differences at steady state and in diseases. J Leukoc Biol 2021; 110:771-796. [PMID: 33600012 DOI: 10.1002/jlb.3ru1120-773r] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 01/04/2021] [Accepted: 01/04/2021] [Indexed: 12/11/2022] Open
Abstract
Although IL-34 and CSF-1 share actions as key mediators of monocytes/macrophages survival and differentiation, they also display differences that should be identified to better define their respective roles in health and diseases. IL-34 displays low sequence homology with CSF-1 but has a similar general structure and they both bind to a common receptor CSF-1R, although binding and subsequent intracellular signaling shows differences. CSF-1R expression has been until now mainly described at a steady state in monocytes/macrophages and myeloid dendritic cells, as well as in some cancers. IL-34 has also 2 other receptors, protein-tyrosine phosphatase zeta (PTPζ) and CD138 (Syndecan-1), expressed in some epithelium, cells of the central nervous system (CNS), as well as in numerous cancers. While most, if not all, of CSF-1 actions are mediated through monocyte/macrophages, IL-34 has also other potential actions through PTPζ and CD138. Additionally, IL-34 and CSF-1 are produced by different cells in different tissues. This review describes and discusses similarities and differences between IL-34 and CSF-1 at steady state and in pathological situations and identifies possible ways to target IL-34, CSF-1, and its receptors.
Collapse
Affiliation(s)
- Antoine Freuchet
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France.,Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France
| | - Apolline Salama
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France.,Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France
| | - Séverine Remy
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France.,Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France
| | - Carole Guillonneau
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France.,Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France
| | - Ignacio Anegon
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France.,Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France
| |
Collapse
|
|
38
|
Jardine L, Cytlak U, Gunawan M, Reynolds G, Green K, Wang XN, Pagan S, Paramitha M, Lamb CA, Long AK, Hurst E, Nair S, Jackson GH, Publicover A, Bigley V, Haniffa M, Simpson AJ, Collin M. Donor monocyte-derived macrophages promote human acute graft-versus-host disease. J Clin Invest 2021; 130:4574-4586. [PMID: 32453711 PMCID: PMC7456218 DOI: 10.1172/jci133909] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Accepted: 05/19/2020] [Indexed: 12/16/2022] Open
Abstract
Myelopoiesis is invariably present and contributes to pathology in animal models of graft-versus-host disease (GVHD). In humans, a rich inflammatory infiltrate bearing macrophage markers has also been described in histological studies. In order to determine the origin, functional properties, and role in pathogenesis of these cells, we isolated single-cell suspensions from acute cutaneous GVHD and subjected them to genotype, transcriptome, and in vitro functional analysis. A donor-derived population of CD11c+CD14+ cells was the dominant population of all leukocytes in GVHD. Surface phenotype and NanoString gene expression profiling indicated the closest steady-state counterpart of these cells to be monocyte-derived macrophages. In GVHD, however, there was upregulation of monocyte antigens SIRPα and S100A8/9 transcripts associated with leukocyte trafficking, pattern recognition, antigen presentation, and costimulation. Isolated GVHD macrophages stimulated greater proliferation and activation of allogeneic T cells and secreted higher levels of inflammatory cytokines than their steady-state counterparts. In HLA-matched mixed leukocyte reactions, we also observed differentiation of activated macrophages with a similar phenotype. These exhibited cytopathicity to a keratinocyte cell line and mediated pathological damage to skin explants independently of T cells. Together, these results define the origin, functional properties, and potential pathogenic roles of human GVHD macrophages.
Collapse
Affiliation(s)
- Laura Jardine
- Human Dendritic Cell Laboratory, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.,Northern Centre for Bone Marrow Transplantation and.,NIHR Newcastle Biomedical Research Centre, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Urszula Cytlak
- Human Dendritic Cell Laboratory, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Merry Gunawan
- Human Dendritic Cell Laboratory, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Gary Reynolds
- NIHR Newcastle Biomedical Research Centre, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.,Institute of Cellular Medicine and
| | - Kile Green
- Human Dendritic Cell Laboratory, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
| | | | - Sarah Pagan
- Human Dendritic Cell Laboratory, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Maharani Paramitha
- Human Dendritic Cell Laboratory, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Christopher A Lamb
- NIHR Newcastle Biomedical Research Centre, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.,Institute of Cellular Medicine and
| | - Anna K Long
- NIHR Newcastle Biomedical Research Centre, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.,Institute of Cellular Medicine and
| | - Erin Hurst
- Northern Centre for Bone Marrow Transplantation and
| | - Smeera Nair
- Northern Centre for Bone Marrow Transplantation and
| | - Graham H Jackson
- Northern Centre for Bone Marrow Transplantation and.,Northern Institute of Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Amy Publicover
- Human Dendritic Cell Laboratory, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.,Northern Centre for Bone Marrow Transplantation and.,NIHR Newcastle Biomedical Research Centre, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Venetia Bigley
- Human Dendritic Cell Laboratory, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.,Northern Centre for Bone Marrow Transplantation and.,NIHR Newcastle Biomedical Research Centre, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Muzlifah Haniffa
- NIHR Newcastle Biomedical Research Centre, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.,Institute of Cellular Medicine and
| | - A J Simpson
- NIHR Newcastle Biomedical Research Centre, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.,Institute of Cellular Medicine and
| | - Matthew Collin
- Human Dendritic Cell Laboratory, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.,Northern Centre for Bone Marrow Transplantation and.,NIHR Newcastle Biomedical Research Centre, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| |
Collapse
|
|
39
|
Zhang F, Zhang J, Cao P, Sun Z, Wang W. The characteristics of regulatory macrophages and their roles in transplantation. Int Immunopharmacol 2021; 91:107322. [PMID: 33418238 DOI: 10.1016/j.intimp.2020.107322] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Revised: 11/25/2020] [Accepted: 12/16/2020] [Indexed: 12/24/2022]
Abstract
Regulatory macrophages (Mregs) are a subtype of macrophages that are involved in regulating immune responses and inhibiting activated T lymphocyte proliferation. With advances in our basic understanding of Mregs and the revelation of their biological characteristics, Mregs have become a focus of research. In addition to promoting malignant tumor progression, Mregs also play an immunosuppressive role in inflammatory diseases and transplantation. Recent studies have shown that Mregs are closely associated with the induction of transplantation immune tolerance. Immune regulatory cell treatment as an adjunct immunosuppressive therapy offers new insights into the mechanism by which transplantation immune tolerance is established. The application of Mreg-based cellular immunotherapy has shown promise in clinical solid organ transplantation. Here, we provide a comprehensive overview of Mreg morphology, phenotype, induction and negative immunoregulatory function and discuss the role of Mregs in different transplantation models as well as their potential application value in clinical organ transplantation.
Collapse
Affiliation(s)
- Feilong Zhang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China.
| | - Jiandong Zhang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Peng Cao
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Zejia Sun
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Wei Wang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China.
| |
Collapse
|
|
40
|
Naserian S, Leclerc M, Shamdani S, Uzan G. Current Preventions and Treatments of aGVHD: From Pharmacological Prophylaxis to Innovative Therapies. Front Immunol 2020; 11:607030. [PMID: 33391276 PMCID: PMC7773902 DOI: 10.3389/fimmu.2020.607030] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 11/16/2020] [Indexed: 12/16/2022] Open
Abstract
Graft versus host disease (GVHD) is one of the main causes of mortality and the reason for up to 50% of morbidity after hematopoietic stem cell transplantations (HSCT) which is the treatment of choice for many blood malignancies. Thanks to years of research and exploration, we have acquired a profound understanding of the pathophysiology and immunopathology of these disorders. This led to the proposition and development of many therapeutic approaches during the last decades, some of them with very promising results. In this review, we have focused on the recent GVHD treatments from classical chemical and pharmacological prophylaxis to more innovative treatments including gene therapy and cell therapy, most commonly based on the application of a variety of immunomodulatory cells. Furthermore, we have discussed the advantages and potentials of cell-free therapy as a newly emerging approach to treat GVHD. Among them, we have particularly focused on the implication of the TNFα-TNFR2 axis as a new immune checkpoint signaling pathway controlling different aspects of many immunoregulatory cells.
Collapse
Affiliation(s)
- Sina Naserian
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France
- Paris-Saclay University, Villejuif, France
- CellMedEx, Saint Maur Des Fossés, France
| | - Mathieu Leclerc
- Service d’Hématologie Clinique et de Thérapie Cellulaire, Hôpital Henri Mondor, Créteil, France
- INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France
- Faculté de Médecine de Créteil, Université Paris-Est, Créteil, France
| | - Sara Shamdani
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France
- Paris-Saclay University, Villejuif, France
- CellMedEx, Saint Maur Des Fossés, France
| | - Georges Uzan
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France
- Paris-Saclay University, Villejuif, France
| |
Collapse
|
|
41
|
Lacerda Mariano L, Rousseau M, Varet H, Legendre R, Gentek R, Saenz Coronilla J, Bajenoff M, Gomez Perdiguero E, Ingersoll MA. Functionally distinct resident macrophage subsets differentially shape responses to infection in the bladder. SCIENCE ADVANCES 2020; 6:6/48/eabc5739. [PMID: 33239294 PMCID: PMC7688323 DOI: 10.1126/sciadv.abc5739] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 10/15/2020] [Indexed: 05/11/2023]
Abstract
Resident macrophages are abundant in the bladder, playing key roles in immunity to uropathogens. Yet, whether they are heterogeneous, where they come from, and how they respond to infection remain largely unknown. We identified two macrophage subsets in mouse bladders, MacM in muscle and MacL in the lamina propria, each with distinct protein expression and transcriptomes. Using a urinary tract infection model, we validated our transcriptomic analyses, finding that MacM macrophages phagocytosed more bacteria and polarized to an anti-inflammatory profile, whereas MacL macrophages died rapidly during infection. During resolution, monocyte-derived cells contributed to tissue-resident macrophage pools and both subsets acquired transcriptional profiles distinct from naïve macrophages. Macrophage depletion resulted in the induction of a type 1-biased immune response to a second urinary tract infection, improving bacterial clearance. Our study uncovers the biology of resident macrophages and their responses to an exceedingly common infection in a largely overlooked organ, the bladder.
Collapse
Affiliation(s)
- Livia Lacerda Mariano
- Department of Immunology, Institut Pasteur, 75015 Paris, France
- INSERM U1223 Paris, France
| | - Matthieu Rousseau
- Department of Immunology, Institut Pasteur, 75015 Paris, France
- INSERM U1223 Paris, France
| | - Hugo Varet
- Bioinformatic and Biostatistic Hub, Department of Computational Biology, Institut Pasteur, USR 3756 CNRS, Paris, France
- Biomics Platform, Center for Technological Resources and Research (C2RT), Institut Pasteur, Paris, France
| | - Rachel Legendre
- Bioinformatic and Biostatistic Hub, Department of Computational Biology, Institut Pasteur, USR 3756 CNRS, Paris, France
- Biomics Platform, Center for Technological Resources and Research (C2RT), Institut Pasteur, Paris, France
| | - Rebecca Gentek
- Aix Marseille University, CNRS, INSERM, CIML, Marseille, France
| | - Javier Saenz Coronilla
- Macrophages and Endothelial Cells, Department of Developmental and Stem Cell Biology, CNRS UMR3738, Department of Immunology, Institut Pasteur, Paris, France
| | - Marc Bajenoff
- Aix Marseille University, CNRS, INSERM, CIML, Marseille, France
| | - Elisa Gomez Perdiguero
- Macrophages and Endothelial Cells, Department of Developmental and Stem Cell Biology, CNRS UMR3738, Department of Immunology, Institut Pasteur, Paris, France
| | - Molly A Ingersoll
- Department of Immunology, Institut Pasteur, 75015 Paris, France.
- INSERM U1223 Paris, France
| |
Collapse
|
|
42
|
Donor T-cell-derived GM-CSF drives alloantigen presentation by dendritic cells in the gastrointestinal tract. Blood Adv 2020; 3:2859-2865. [PMID: 31585949 DOI: 10.1182/bloodadvances.2019000053] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 08/22/2019] [Indexed: 11/20/2022] Open
Abstract
Granulocyte-macrophage colony-stimulating factor (GM-CSF) has recently emerged as an important pathogenic cytokine in acute graft-versus-host disease (GVHD), but the nature of the T-cell lineages secreting the cytokine and the mechanisms of action are less clear. Here we used interleukin 17A-fate reporter systems with transcriptional analysis and assays of alloantigen presentation to interrogate the origins of GM-CSF-secreting T cells and the effects of the cytokine on antigen-presenting cell (APC) function after experimental allogeneic stem cell transplantation (SCT). We demonstrated that although GM-CSF-secreting Th17 and non-Th17 cells expanded in the colon over time after SCT, the Th17 lineage expanded to represent 10% to 20% of the GM-CSF secreting T cells at this site by 4 weeks. Donor T-cell-derived GM-CSF expanded alloantigen-presenting donor dendritic cells (DCs) in the colon and lymph nodes. In the mesenteric lymph nodes, GM-CSF-dependent DCs primed donor T cells and amplified acute GVHD in the colon. We thus describe a feed-forward cascade whereby GM-CSF-secreting donor T cells accumulate and drive alloantigen presentation in the colon to amplify GVHD severity. GM-CSF inhibition may be a tractable clinical intervention to limit donor alloantigen presentation and GVHD in the lower gastrointestinal tract.
Collapse
|
|
43
|
Liu Q, Zhang Y, Zhang J, Tao K, Hambly BD, Bao S. Inverse correlation between Interleukin-34 and gastric cancer, a potential biomarker for prognosis. Cell Biosci 2020; 10:94. [PMID: 32765828 PMCID: PMC7399616 DOI: 10.1186/s13578-020-00454-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 07/25/2020] [Indexed: 12/17/2022] Open
Abstract
Background Gastric cancer (GC) is a malignancy with high morbidity/mortality, partly due to a lack of reliable biomarkers for early diagnosis. It is important to develop reliable biomarker(s) with specificity, sensitivity and convenience for early diagnosis. The role of tumour-associated macrophages (TAMs) and survival of GC patients are controversial. Macrophage colony stimulating factor (MCSF) regulates monocytes/macrophages. Elevated MCSF is correlated with invasion, metastasis and poor survival of tumour patients. IL-34, a ligand of the M-CSF receptor, acts as a “twin” to M-CSF, demonstrating overlapping and complimentary actions. IL-34 involvement in tumours is controversial, possibly due to the levels of M-CSF receptors. While the IL-34/M-CSF/M-CSFR axis is very important for regulating macrophage differentiation, the specific interplay between these cytokines, macrophages and tumour development is unclear. Methods A multi-factorial evaluation could provide more objective utility, particularly for either prediction and/or prognosis of gastric cancer. Precision medicine requires molecular diagnosis to determine the specifically mutant function of tumours, and is becoming popular in the treatment of malignancy. Therefore, elucidating specific molecular signalling pathways in specific cancers facilitates the success of a precision medicine approach. Gastric cancer tissue arrays were generated from stomach samples with TNM stage, invasion depth and the demography of these patients (n = 185). Using immunohistochemistry/histopathology, M-CSF, IL-34 and macrophages were determined. Results We found that IL-34 may serve as a predictive biomarker, but not as an independent, prognostic factor in GC; M-CSF inversely correlated with survival of GC in TNM III–IV subtypes. Increased CD68+ TAMs were a good prognostic factor in some cases and could be used as an independent prognostic factor in male T3 stage GC. Conclusion Our data support the potency of IL-34, M-CSF, TAMs and the combination of IL-34/TAMs as novel biological markers for GC, and may provide new insight for both diagnosis and cellular therapy of GC.
Collapse
Affiliation(s)
- Qinghua Liu
- Department of Pathology, Xuzhou Medical University, Xuzhou, 221000 China.,Discipline of Pathology, Bosch Institute and School of Medical Sciences, Charles Perkins Center D17, Sydney Medical School, The University of Sydney, Sydney, NSW 2006 Australia
| | - Ying Zhang
- Department of Pathology, Xuzhou Medical University, Xuzhou, 221000 China
| | - Jiwei Zhang
- Department of Surgery, Songjiang Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 201600 China
| | - Kun Tao
- Tongren Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, 200336 China
| | - Brett D Hambly
- Discipline of Pathology, Bosch Institute and School of Medical Sciences, Charles Perkins Center D17, Sydney Medical School, The University of Sydney, Sydney, NSW 2006 Australia.,Tongren Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, 200336 China
| | - Shisan Bao
- Discipline of Pathology, Bosch Institute and School of Medical Sciences, Charles Perkins Center D17, Sydney Medical School, The University of Sydney, Sydney, NSW 2006 Australia.,Tongren Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, 200336 China
| |
Collapse
|
|
44
|
Einwächter H, Heiseke A, Schlitzer A, Gasteiger G, Adler H, Voehringer D, Manz MG, Ruzsics Z, Dölken L, Koszinowski UH, Sparwasser T, Reindl W, Jordan S. The Innate Immune Response to Infection Induces Erythropoietin-Dependent Replenishment of the Dendritic Cell Compartment. Front Immunol 2020; 11:1627. [PMID: 32849551 PMCID: PMC7411349 DOI: 10.3389/fimmu.2020.01627] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Accepted: 06/17/2020] [Indexed: 12/29/2022] Open
Abstract
Dendritic cells (DC) play a key role in the adaptive immune response due to their ability to present antigens and stimulate naïve T cells. Many bacteria and viruses can efficiently target DC, resulting in impairment of their immunostimulatory function or elimination. Hence, the DC compartment requires replenishment following infection to ensure continued operational readiness of the adaptive immune system. Here, we investigated the molecular and cellular mechanisms of inflammation-induced DC generation. We found that infection with viral and bacterial pathogens as well as Toll-like receptor 9 (TLR9) ligation with CpG-oligodeoxynucleotide (CpG-ODN) expanded an erythropoietin (EPO)-dependent TER119+CD11a+ cell population in the spleen that had the capacity to differentiate into TER119+CD11chigh and TER119-CD11chigh cells both in vitro and in vivo. TER119+CD11chigh cells contributed to the conventional DC pool in the spleen and specifically increased in lymph nodes draining the site of local inflammation. Our results reveal a so far undescribed inflammatory EPO-dependent pathway of DC differentiation and establish a mechanistic link between innate immune recognition of potential immunosuppressive pathogens and the maintenance of the DC pool during and after infection.
Collapse
Affiliation(s)
- Henrik Einwächter
- II. Medizinische Klinik, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
| | - Alexander Heiseke
- II. Medizinische Klinik, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
| | | | - Georg Gasteiger
- Institute of Systems Immunology, Julius-Maximilians-University Würzburg, Würzburg, Germany
| | - Heiko Adler
- Comprehensive Pneumology Center, Research Unit Lung Repair and Regeneration, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Munich, Germany.,German Center of Lung Research (DZL), Giessen, Germany
| | - David Voehringer
- Department of Infection Biology, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Nürnberg, Erlangen, Germany
| | - Markus G Manz
- Division of Hematology, Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland
| | - Zsolt Ruzsics
- Institute of Virology, University Medical Center, Medical Faculty, University of Freiburg, Freiburg, Germany
| | - Lars Dölken
- Institute for Virology and Immunobiology, Julius-Maximilians-University Würzburg, Würzburg, Germany
| | - Ulrich H Koszinowski
- Max von Pettenkofer-Institute, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Tim Sparwasser
- Institute of Medical Microbiology and Hygiene, University Medicine Mainz, Johannes-Gutenberg-University Mainz, Mainz, Germany
| | - Wolfgang Reindl
- II. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany
| | - Stefan Jordan
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Microbiology, Infectious Diseases and Immunology, Berlin, Germany
| |
Collapse
|
|
45
|
Seyfried AN, Maloney JM, MacNamara KC. Macrophages Orchestrate Hematopoietic Programs and Regulate HSC Function During Inflammatory Stress. Front Immunol 2020; 11:1499. [PMID: 32849512 PMCID: PMC7396643 DOI: 10.3389/fimmu.2020.01499] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 06/08/2020] [Indexed: 12/14/2022] Open
Abstract
The bone marrow contains distinct cell types that work in coordination to generate blood and immune cells, and it is the primary residence of hematopoietic stem cells (HSCs) and more committed multipotent progenitors (MPPs). Even at homeostasis the bone marrow is a dynamic environment where billions of cells are generated daily to replenish short-lived immune cells and produce the blood factors and cells essential for hemostasis and oxygenation. In response to injury or infection, the marrow rapidly adapts to produce specific cell types that are in high demand revealing key insight to the inflammatory nature of "demand-adapted" hematopoiesis. Here we focus on the role that resident and monocyte-derived macrophages play in driving these hematopoietic programs and how macrophages impact HSCs and downstream MPPs. Macrophages are exquisite sensors of inflammation and possess the capacity to adapt to the environment, both promoting and restraining inflammation. Thus, macrophages hold great potential for manipulating hematopoietic output and as potential therapeutic targets in a variety of disease states where macrophage dysfunction contributes to or is necessary for disease. We highlight essential features of bone marrow macrophages and discuss open questions regarding macrophage function, their role in orchestrating demand-adapted hematopoiesis, and mechanisms whereby they regulate HSC function.
Collapse
Affiliation(s)
- Allison N Seyfried
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY, United States
| | - Jackson M Maloney
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY, United States
| | - Katherine C MacNamara
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY, United States
| |
Collapse
|
|
46
|
Hong YQ, Wan B, Li XF. Macrophage regulation of graft- vs-host disease. World J Clin Cases 2020; 8:1793-1805. [PMID: 32518770 PMCID: PMC7262718 DOI: 10.12998/wjcc.v8.i10.1793] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 04/08/2020] [Accepted: 04/21/2020] [Indexed: 02/05/2023] Open
Abstract
Hematopoietic stem cell transplantation has become a curative choice of many hematopoietic malignancy, but graft-vs-host disease (GVHD) has limited the survival quality and overall survival of hematopoietic stem cell transplantation. Understanding of the immune cells’ reaction in pathophysiology of GVHD has improved, but a review on the role of macrophages in GVHD is still absent. Studies have observed that macrophage infiltration is associated with GVHD occurrence and development. In this review, we summarize and analyze the role of macrophages in GVHD based on pathophysiology of acute and chronic GVHD, focusing on the macrophage recruitment and infiltration, macrophage polarization, macrophage secretion, and especially interaction of macrophages with other immune cells. We could conclude that macrophage recruitment and infiltration contribute to both acute and chronic GVHD. Based on distinguishing pathology of acute and chronic GVHD, macrophages tend to show a higher M1/M2 ratio in acute GVHD and a lower M1/M2 ratio in chronic GVHD. However, the influence of dominant cytokines in GVHD is controversial and inconsistent with macrophage polarization. In addition, interaction of macrophages with alloreactive T cells plays an important role in acute GVHD. Meanwhile, the interaction among macrophages, B cells, fibroblasts, and CD4+ T cells participates in chronic GVHD development.
Collapse
Affiliation(s)
- Ya-Qun Hong
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Department of Hematology, Fujian Medical University Union Hospital, Fuzhou 350000, Fujian Province, China
| | - Bo Wan
- Faculty of Life Sciences and Medicine, King’s College London, London WC1N 3BG, United Kingdom
| | - Xiao-Fan Li
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Department of Hematology, Fujian Medical University Union Hospital, Fuzhou 350000, Fujian Province, China
- INSERM U1160, Hospital Saint Louis, Université Paris Diderot, Paris 94430, France
| |
Collapse
|
|
47
|
The primacy of gastrointestinal tract antigen-presenting cells in lethal graft-versus-host disease. Blood 2020; 134:2139-2148. [PMID: 31697827 DOI: 10.1182/blood.2019000823] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 10/24/2019] [Indexed: 12/26/2022] Open
Abstract
Allogeneic stem cell transplantation is a cornerstone of curative therapy for high-risk and/or advanced hematological malignancies but remains limited by graft-versus-host disease (GVHD). GVHD is initiated by the interaction between recipient antigen-presenting cells (APCs) and donor T cells, culminating in T-cell differentiation along pathogenic type-1 and type-17 paradigms at the expense of tolerogenic regulatory T-cell patterns. Type-1 and type-17 T cells secrete cytokines (eg, granulocyte-macrophage colony-stimulating factor and interferon-γ) critical to the cytokine storm that amplifies expansion of donor APCs and their alloantigen presentation. It has become increasingly clear that pathogenic donor T-cell differentiation is initiated by both professional recipient APCs (eg, dendritic cells [DCs]) and nonprofessional APCs (eg, epithelial and mesenchymal cells), particularly within the gastrointestinal (GI) tract. In the immediate peritransplantation period, these APCs are profoundly modified by pathogen-associated molecular pattern (PAMP)/damage-associated molecular pattern (DAMP) signals derived from conditioning and intestinal microbiota. Subsequently, donor DCs in the GI tract are activated by DAMP/PAMP signals in the colon that gain access to the lamina propria once the mucosal barrier mucosa is compromised by GVHD. This results in donor DC expansion and alloantigen presentation in the colon and subsequent migration into the mesenteric lymph nodes. Here, new donor T cells are primed, expanded, differentiated, and imprinted with gut-homing integrins permissive of migration into the damaged GI tract, resulting in the lethal feed-forward cascade of GVHD. These new insights into our understanding of the cellular and molecular factors initiating GVHD, both spatially and temporally, give rise to a number of logical therapeutic targets, focusing on the inhibition of APC function in the GI tract.
Collapse
|
|
48
|
Schwarzer P, Kokona D, Ebneter A, Zinkernagel MS. Effect of Inhibition of Colony-Stimulating Factor 1 Receptor on Choroidal Neovascularization in Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 190:412-425. [PMID: 31783006 DOI: 10.1016/j.ajpath.2019.10.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 07/09/2019] [Accepted: 10/21/2019] [Indexed: 12/15/2022]
Abstract
Neovascular age-related macular degeneration is one of the leading causes of blindness. Microglia and macrophages play a critical role in choroidal neovascularization (CNV) and may, therefore, be potential targets to modulate the disease course. This study evaluated the effect of the colony-stimulating factor-1 receptor inhibitor PLX5622 on experimental laser-induced CNV. A 98% reduction of retinal microglia cells was observed in the retina 1 week after initiation of PLX5622 treatment, preventing accumulation of macrophages within the laser site and leading to a reduction of leukocytes within the choroid after CNV induction. Mice treated with PLX5622 had a significantly faster decrease of the CNV lesion size, as revealed by in vivo imaging and immunohistochemistry from day 3 to day 14 compared with untreated mice. Several inflammatory modulators, such as chemokine (C-C motif) ligand 9, granulocyte-macrophage colony-stimulating factor, soluble tumor necrosis factor receptor-I, IL-1α, and matrix metallopeptidase-2, were elevated in the acute phase of the disease when microglia were ablated with PLX5622, whereas other cytokines (eg, interferon-γ, IL-4, and IL-10) were reduced. Our results suggest that colony-stimulating factor-1 receptor inhibition may be a novel therapeutic target in patients with neovascular age-related macular degeneration.
Collapse
Affiliation(s)
- Petra Schwarzer
- Department of Ophthalmology, Inselspital, Bern University Hospital, University of Bern, Bern; and the Department for BioMedical Research, University of Bern, Bern, Switzerland
| | - Despina Kokona
- Department of Ophthalmology, Inselspital, Bern University Hospital, University of Bern, Bern; and the Department for BioMedical Research, University of Bern, Bern, Switzerland
| | - Andreas Ebneter
- Department of Ophthalmology, Inselspital, Bern University Hospital, University of Bern, Bern; and the Department for BioMedical Research, University of Bern, Bern, Switzerland
| | - Martin S Zinkernagel
- Department of Ophthalmology, Inselspital, Bern University Hospital, University of Bern, Bern; and the Department for BioMedical Research, University of Bern, Bern, Switzerland.
| |
Collapse
|
|
49
|
Koyama M, Mukhopadhyay P, Schuster IS, Henden AS, Hülsdünker J, Varelias A, Vetizou M, Kuns RD, Robb RJ, Zhang P, Blazar BR, Thomas R, Begun J, Waddell N, Trinchieri G, Zeiser R, Clouston AD, Degli-Esposti MA, Hill GR. MHC Class II Antigen Presentation by the Intestinal Epithelium Initiates Graft-versus-Host Disease and Is Influenced by the Microbiota. Immunity 2019; 51:885-898.e7. [PMID: 31542340 DOI: 10.1016/j.immuni.2019.08.011] [Citation(s) in RCA: 174] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 05/15/2019] [Accepted: 08/13/2019] [Indexed: 12/30/2022]
Abstract
Graft-versus-host disease (GVHD) in the gastrointestinal (GI) tract is the principal determinant of lethality following allogeneic bone marrow transplantation (BMT). Here, we examined the mechanisms that initiate GVHD, including the relevant antigen-presenting cells. MHC class II was expressed on intestinal epithelial cells (IECs) within the ileum at steady state but was absent from the IECs of germ-free mice. IEC-specific deletion of MHC class II prevented the initiation of lethal GVHD in the GI tract. MHC class II expression on IECs was absent from mice deficient in the TLR adaptors MyD88 and TRIF and required IFNγ secretion by lamina propria lymphocytes. IFNγ responses are characteristically driven by IL-12 secretion from myeloid cells. Antibiotic-mediated depletion of the microbiota inhibited IL-12/23p40 production by ileal macrophages. IL-12/23p40 neutralization prevented MHC class II upregulation on IECs and initiation of lethal GVHD in the GI tract. Thus, MHC class II expression by IECs in the ileum initiates lethal GVHD, and blockade of IL-12/23p40 may represent a readily translatable therapeutic strategy.
Collapse
Affiliation(s)
- Motoko Koyama
- Bone Marrow Transplantation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
| | - Pamela Mukhopadhyay
- Medical Genomics Laboratory, Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
| | - Iona S Schuster
- Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA 6009, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA 6009, Australia; Infection and Immunity Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
| | - Andrea S Henden
- Bone Marrow Transplantation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; Department of Haematology and Bone Marrow Transplantation, Cancer Care Services, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia
| | - Jan Hülsdünker
- Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Albert Ludwigs University Freiburg, Freiburg 79106, Germany; Spemann Graduate School of Biology and Medicine, University Freiburg, Freiburg 79085, Germany; Faculty of Biology, University Freiburg, Freiburg 79104, Germany
| | - Antiopi Varelias
- Bone Marrow Transplantation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
| | - Marie Vetizou
- Cancer and Inflammation Program, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
| | - Rachel D Kuns
- Bone Marrow Transplantation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
| | - Renee J Robb
- Bone Marrow Transplantation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
| | - Ping Zhang
- Bone Marrow Transplantation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
| | - Bruce R Blazar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA
| | - Ranjeny Thomas
- Diamantina Institute, Translational Research Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, QLD 4102, Australia
| | - Jakob Begun
- Mater Research Institute, University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia
| | - Nicola Waddell
- Medical Genomics Laboratory, Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
| | - Giorgio Trinchieri
- Cancer and Inflammation Program, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
| | - Robert Zeiser
- Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Albert Ludwigs University Freiburg, Freiburg 79106, Germany
| | | | - Mariapia A Degli-Esposti
- Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA 6009, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA 6009, Australia; Infection and Immunity Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
| | - Geoffrey R Hill
- Bone Marrow Transplantation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; Department of Haematology and Bone Marrow Transplantation, Cancer Care Services, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Division of Medical Oncology, University of Washington, Seattle, WA 98109, USA.
| |
Collapse
|
|
50
|
Ponzetta A, Carriero R, Carnevale S, Barbagallo M, Molgora M, Perucchini C, Magrini E, Gianni F, Kunderfranco P, Polentarutti N, Pasqualini F, Di Marco S, Supino D, Peano C, Cananzi F, Colombo P, Pilotti S, Alomar SY, Bonavita E, Galdiero MR, Garlanda C, Mantovani A, Jaillon S. Neutrophils Driving Unconventional T Cells Mediate Resistance against Murine Sarcomas and Selected Human Tumors. Cell 2019; 178:346-360.e24. [PMID: 31257026 PMCID: PMC6630709 DOI: 10.1016/j.cell.2019.05.047] [Citation(s) in RCA: 179] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 04/15/2019] [Accepted: 05/22/2019] [Indexed: 02/07/2023]
Abstract
Neutrophils are a component of the tumor microenvironment and have been predominantly associated with cancer progression. Using a genetic approach complemented by adoptive transfer, we found that neutrophils are essential for resistance against primary 3-methylcholantrene-induced carcinogenesis. Neutrophils were essential for the activation of an interferon-γ-dependent pathway of immune resistance, associated with polarization of a subset of CD4- CD8- unconventional αβ T cells (UTCαβ). Bulk and single-cell RNA sequencing (scRNA-seq) analyses unveiled the innate-like features and diversity of UTCαβ associated with neutrophil-dependent anti-sarcoma immunity. In selected human tumors, including undifferentiated pleomorphic sarcoma, CSF3R expression, a neutrophil signature and neutrophil infiltration were associated with a type 1 immune response and better clinical outcome. Thus, neutrophils driving UTCαβ polarization and type 1 immunity are essential for resistance against murine sarcomas and selected human tumors.
Collapse
Affiliation(s)
- Andrea Ponzetta
- Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy; Humanitas Clinical and Research Center, 20089 Rozzano, Italy
| | | | - Silvia Carnevale
- Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy
| | | | - Martina Molgora
- Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy
| | | | - Elena Magrini
- Humanitas Clinical and Research Center, 20089 Rozzano, Italy
| | - Francesca Gianni
- Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA
| | | | - Nadia Polentarutti
- Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy
| | - Fabio Pasqualini
- Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy
| | - Sabrina Di Marco
- Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy
| | - Domenico Supino
- Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy
| | - Clelia Peano
- Humanitas Clinical and Research Center, 20089 Rozzano, Italy; Institute of Genetic and Biomedical Research, UoS Milan, National Research Council, 20089 Rozzano, Italy
| | - Ferdinando Cananzi
- Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy; Surgical Oncology Unit, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, Italy
| | | | - Silvana Pilotti
- Pathology Department, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy
| | - Suliman Yousef Alomar
- Zoology Department College of Science, King Saud University, 12372 Riyadh, Saudi Arabia
| | - Eduardo Bonavita
- Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park SK10 4GT, UK
| | - Maria Rosaria Galdiero
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80138 Naples, Italy
| | - Cecilia Garlanda
- Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy; Humanitas Clinical and Research Center, 20089 Rozzano, Italy
| | - Alberto Mantovani
- Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy; Humanitas Clinical and Research Center, 20089 Rozzano, Italy; The William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, UK.
| | - Sebastien Jaillon
- Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy; Humanitas Clinical and Research Center, 20089 Rozzano, Italy.
| |
Collapse
|