|
1
|
Monel B, Lamothe PA, Meyo J, McLean AP, Quinones-Alvarado R, Laporte M, Boucau J, Walker BD, Kavanagh DG, Garcia-Beltran WF, Pacheco Y. SLAMF6 enables efficient attachment, synapse formation, and killing of HIV-1-infected CD4 + T cells by virus-specific CD8 + T cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.20.633914. [PMID: 39896504 PMCID: PMC11785116 DOI: 10.1101/2025.01.20.633914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Efficient recognition and elimination of HIV-1-infected CD4+ T cells by cytotoxic CD8+ T cells (CTLs) require target cell engagement and the formation of a well-organized immunological synapse. Surface proteins belonging to the SLAM family are known to be crucial for stabilizing the immunological synapse and regulating antiviral responses during lymphotropic viral infections. In the context of HIV-1, there have been reports of SLAMF6 down-regulation in HIV-1-infected CD4+ T cells; however, the significance of this modulation for CTL function remains unclear. In this investigation, we used CTL lines from People living with HIV (PLWH) to examine the impact of SLAMF6 blockade on three pivotal processes: (1) the formation of CD8+-CD4+ T-cell conjugates, (2) the establishment of the immunological synapse, and (3) the killing and cytokine production capacity of HIV-1-specific CTLs during HIV-1 infection. Our findings reveal that the inability to form CD8+-CD4+ T-cell conjugates following incubation with an anti-SLAMF6 blocking antibody is primarily attributable to a defect in actin ring formation at the immunological synapse. Furthermore, SLAMF6 blockade leads to a reduction in the killing efficiency of HIV-1-infected CD4+ T cells by HIV-1-specific CTLs, underscoring the critical role of SLAMF6 in cytolytic function. This study highlights the importance of SLAMF6 receptors in modulating cytotoxic antiviral responses, shedding light on potential avenues for manipulation and enhancement of this pathway in the context of HIV and other lymphotropic viral infections.
Collapse
Affiliation(s)
- Blandine Monel
- Ragon Institute of Mass General, MIT and Harvard, Cambridge, Massachusetts, USA
- Howard Hughes Medical Institute, Chevy Chase, Maryland, USA
- Nantes Université, Univ Angers, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT, UMR 1302/EMR6001, F-44000 Nantes, France
| | - Pedro A. Lamothe
- Ragon Institute of Mass General, MIT and Harvard, Cambridge, Massachusetts, USA
- Howard Hughes Medical Institute, Chevy Chase, Maryland, USA
- Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine. Emory University School of Medicine. Atlanta, Georgia, USA
| | - James Meyo
- Ragon Institute of Mass General, MIT and Harvard, Cambridge, Massachusetts, USA
- EMD Serono, Boston, Massachusetts, USA
| | - Anna P. McLean
- Ragon Institute of Mass General, MIT and Harvard, Cambridge, Massachusetts, USA
- Maine Medical Center, Department of Psychiatry
| | | | - Mélanie Laporte
- Nantes Université, Univ Angers, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT, UMR 1302/EMR6001, F-44000 Nantes, France
| | - Julie Boucau
- Ragon Institute of Mass General, MIT and Harvard, Cambridge, Massachusetts, USA
| | - Bruce D. Walker
- Ragon Institute of Mass General, MIT and Harvard, Cambridge, Massachusetts, USA
- Howard Hughes Medical Institute, Chevy Chase, Maryland, USA
| | - Daniel G. Kavanagh
- Ragon Institute of Mass General, MIT and Harvard, Cambridge, Massachusetts, USA
- WCG, Princeton, New Jersey, USA
| | - Wilfredo F. Garcia-Beltran
- Ragon Institute of Mass General, MIT and Harvard, Cambridge, Massachusetts, USA
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Yovana Pacheco
- Ragon Institute of Mass General, MIT and Harvard, Cambridge, Massachusetts, USA
- Grupo de Investigación INPAC, Fundación Universitaria Sanitas, Bogotá, Colombia
| |
Collapse
|
|
2
|
Matsushima R, Wakamatsu E, Machiyama H, Nishi W, Yoshida Y, Nishikawa T, Toyota H, Furuhata M, Nishijima H, Takeuchi A, Suzuki M, Yokosuka T. Imaging of biphasic signalosomes constructed by checkpoint receptor 2B4 in conventional and chimeric antigen receptor-T cells. iScience 2025; 28:111669. [PMID: 39886466 PMCID: PMC11780131 DOI: 10.1016/j.isci.2024.111669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 06/27/2024] [Accepted: 12/19/2024] [Indexed: 02/01/2025] Open
Abstract
A co-signaling receptor, 2B4, has dual effects in immune cells, but its actual functions in T cells remain elusive. Here, using super-resolution imaging technology with an immunological synapse model, we showed that 2B4 forms "2B4 microclusters" immediately after 2B4-CD48 binding. A lipid phosphatase, SHIP-1, subsequently combined with 2B4 to form coinhibitory signalosomes, leading to the suppression of cytokine production. An activating adapter, SLAM-associated protein (SAP), attenuated the clustering of SHIP-1 and recruited a kinase, Fyn, enhancing the Vav1 signaling pathway as costimulatory signalosomes. Furthermore, we found that a chimeric antigen receptor with a 2B4 tail (2B4-CAR) retained the original signal transduction mechanism of 2B4. With endogenous levels of SAP expression, 2B4-CAR-T cells exposed sufficient antitumor efficacy in vivo without excess cytokine production. Our results may help explain the biphasic feature of 2B4 in T cell responses from the viewpoint of the signalosome and provide a new candidate for CAR development.
Collapse
Affiliation(s)
- Ryohei Matsushima
- Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
- Department of Immunology, Tokyo Medical University, Tokyo 160-8402, Japan
| | - Ei Wakamatsu
- Department of Immunology, Tokyo Medical University, Tokyo 160-8402, Japan
| | - Hiroaki Machiyama
- Department of Immunology, Tokyo Medical University, Tokyo 160-8402, Japan
| | - Wataru Nishi
- Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
- Department of Immunology, Tokyo Medical University, Tokyo 160-8402, Japan
| | - Yosuke Yoshida
- Department of Immunology, Tokyo Medical University, Tokyo 160-8402, Japan
- Department of Nephrology, Tokyo Medical University, Tokyo 160-8402, Japan
| | - Tetsushi Nishikawa
- Department of Immunology, Tokyo Medical University, Tokyo 160-8402, Japan
- Department of Dermatology, Tokyo Medical University, Tokyo 160-0023, Japan
| | - Hiroko Toyota
- Department of Immunology, Tokyo Medical University, Tokyo 160-8402, Japan
| | - Masae Furuhata
- Department of Immunology, Tokyo Medical University, Tokyo 160-8402, Japan
| | - Hitoshi Nishijima
- Department of Immunology, Tokyo Medical University, Tokyo 160-8402, Japan
| | - Arata Takeuchi
- Department of Immunology, Tokyo Medical University, Tokyo 160-8402, Japan
| | - Makoto Suzuki
- Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Tadashi Yokosuka
- Department of Immunology, Tokyo Medical University, Tokyo 160-8402, Japan
| |
Collapse
|
|
3
|
Zhang Z, Zhang Y, Chen Z, Xia L. Emerging roles of SLAMF7 in immune cells and related diseases. Innate Immun 2025; 31:17534259251326700. [PMID: 40091370 PMCID: PMC11912174 DOI: 10.1177/17534259251326700] [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: 10/01/2024] [Revised: 12/21/2024] [Accepted: 02/21/2025] [Indexed: 03/19/2025] Open
Abstract
Immune cells are heterogeneous and perform different functions in different microenvironment, thus playing different roles in different stages of diseases. Studies have shown that immune cells are involved in the pathogenesis of many diseases, and there is a causal association of immune cells with disease states. Signaling Lymphocyte Activation Molecule family (SLAMF) members are a newly appreciated group of specific receptors that are mainly expressed in immune cells and whose role is to regulate the function of immune cells. SLAMF7, also known as CD319, has been widely reported in multiple myeloma, and in recent years, more and more studies have shown that SLAMF7 is widely involved in the function of immune cells and the progression of breast cancer, acquired immune deficiency syndrome, systemic lupus erythematosus and other immune cells-related diseases. However, the mechanisms underlying the regulatory role of SLAMF7 on immune cells, and the impact on the progression of immune cells-related diseases remain poorly elucidated. In this review, we summarize current knowledge about the role of SLAMF7 in immune cells and related diseases such as cancer, infectious disease, autoimmune disease and atherosclerosis, and the therapeutic strategy targeting SLAMF7 is also described. By better understanding the role and regulation of SLAMF7, we hope to provide new insights and directions for improving the diagnosis and treatment of inflammation.
Collapse
Affiliation(s)
- Zheng Zhang
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Ying Zhang
- Department of Biochemistry and Molecular Biology, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Zeyu Chen
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Lin Xia
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China
- Institute of Hematological Disease, Jiangsu University, Zhenjiang, China
| |
Collapse
|
|
4
|
Kwantwi LB, Rosen ST, Querfeld C. The role of signaling lymphocyte activation molecule family receptors in hematologic malignancies. Curr Opin Oncol 2024; 36:449-455. [PMID: 39007334 DOI: 10.1097/cco.0000000000001067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/16/2024]
Abstract
PURPOSE OF REVIEW In this review, we provide an overview of the current understanding of SLAM-family receptors in hematologic malignancies. We highlighted their contribution to the disease pathogenesis and targeting strategies to improve therapeutic outcomes. RECENT FINDINGS Emerging studies have reported the tumor-promoting role of SLAM-family receptors in various hematologic malignancies, including chronic lymphocytic leukemia, acute myeloid leukemia, and multiple myeloma. Specifically, they regulate the interaction between malignant cells and the tumor microenvironment to promote apoptosis resistance, therapeutic resistance, impairment of antitumor and tumor progression. SUMMARY SLAM-family receptors promote the progression of hematologic malignancies by regulating the interaction between malignant cells and the tumor microenvironment. This provides the rationale that SLAM-targeted therapies are appealing strategies to enhance therapeutic outcomes in patients.
Collapse
Affiliation(s)
| | - Steven T Rosen
- Department of Hematology & Hematopoietic Cell Transplantation
- Beckman Research Institute, Duarte, California, USA
| | - Christiane Querfeld
- Department of Pathology
- Department of Hematology & Hematopoietic Cell Transplantation
- Division of Dermatology, City of Hope Medical Center
- Beckman Research Institute, Duarte, California, USA
| |
Collapse
|
|
5
|
Timmerman LM, Hensen LCM, van Eijs MJM, Verheijden RJ, Suijkerbuijk KPM, Meyaard L, van der Vlist M. In vitro T cell responses to PD-1 blockade are reduced by IFN-α but do not predict therapy response in melanoma patients. Cancer Immunol Immunother 2024; 73:181. [PMID: 38967829 PMCID: PMC11226572 DOI: 10.1007/s00262-024-03760-z] [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: 05/08/2024] [Accepted: 06/13/2024] [Indexed: 07/06/2024]
Abstract
PD-1 blockade therapy has revolutionized melanoma treatment, but still not all patients benefit and pre-treatment identification of those patients is difficult. Increased expression of inflammatory markers such as interleukin (IL)-6 in blood of patients correlates with poor treatment response. We set out to study the effect of inflammatory cytokines on PD-1 blockade in vitro. For this, we studied the effect of IL-6 and type I interferon (IFN) in vitro on human T cells in a mixed leukocyte reaction (MLR) in the absence or presence of PD-1 blockade. While IL-6 reduced IFN-γ secretion by T cells in both the presence and absence of PD-1 blockade, IFN-α specifically reduced the IFN-γ secretion only in the presence of PD-1 blockade. IFN-α reduced T cell proliferation independent of PD-1 blockade and reduced the percentage of cells producing IFN-γ only in the presence of PD-1 blockade. Next we determined the type I IFN score in a cohort of 22 melanoma patients treated with nivolumab. In this cohort, we did not find a correlation between clinical response and type I IFN score, nor between clinical response and IFN-γ secretion in vitro in a MLR in the presence of PD-1 blockade. We conclude that IFN-α reduces the effectiveness of PD-1 blockade in vitro, but that in this cohort, type I IFN score in vivo, nor IFN-γ secretion in vitro in a MLR in the presence of PD-1 blockade correlated to decreased therapy responses in patients.
Collapse
Affiliation(s)
- Laura M Timmerman
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
- Oncode Institute, Utrecht, The Netherlands
| | - Lobke C M Hensen
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Mick J M van Eijs
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Rik J Verheijden
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Karijn P M Suijkerbuijk
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Linde Meyaard
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
- Oncode Institute, Utrecht, The Netherlands
| | - Michiel van der Vlist
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
- Oncode Institute, Utrecht, The Netherlands.
| |
Collapse
|
|
6
|
Xiao L, Zhang L, Guo C, Xin Q, Gu X, Jiang C, Wu J. "Find Me" and "Eat Me" signals: tools to drive phagocytic processes for modulating antitumor immunity. Cancer Commun (Lond) 2024; 44:791-832. [PMID: 38923737 PMCID: PMC11260773 DOI: 10.1002/cac2.12579] [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: 12/18/2023] [Revised: 06/03/2024] [Accepted: 06/05/2024] [Indexed: 06/28/2024] Open
Abstract
Phagocytosis, a vital defense mechanism, involves the recognition and elimination of foreign substances by cells. Phagocytes, such as neutrophils and macrophages, rapidly respond to invaders; macrophages are especially important in later stages of the immune response. They detect "find me" signals to locate apoptotic cells and migrate toward them. Apoptotic cells then send "eat me" signals that are recognized by phagocytes via specific receptors. "Find me" and "eat me" signals can be strategically harnessed to modulate antitumor immunity in support of cancer therapy. These signals, such as calreticulin and phosphatidylserine, mediate potent pro-phagocytic effects, thereby promoting the engulfment of dying cells or their remnants by macrophages, neutrophils, and dendritic cells and inducing tumor cell death. This review summarizes the phagocytic "find me" and "eat me" signals, including their concepts, signaling mechanisms, involved ligands, and functions. Furthermore, we delineate the relationships between "find me" and "eat me" signaling molecules and tumors, especially the roles of these molecules in tumor initiation, progression, diagnosis, and patient prognosis. The interplay of these signals with tumor biology is elucidated, and specific approaches to modulate "find me" and "eat me" signals and enhance antitumor immunity are explored. Additionally, novel therapeutic strategies that combine "find me" and "eat me" signals to better bridge innate and adaptive immunity in the treatment of cancer patients are discussed.
Collapse
Affiliation(s)
- Lingjun Xiao
- State Key Laboratory of Pharmaceutical BiotechnologyNational Institute of Healthcare Data Science at Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing UniversityNanjingJiangsuP. R. China
| | - Louqian Zhang
- State Key Laboratory of Pharmaceutical BiotechnologyNational Institute of Healthcare Data Science at Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing UniversityNanjingJiangsuP. R. China
| | - Ciliang Guo
- State Key Laboratory of Pharmaceutical BiotechnologyNational Institute of Healthcare Data Science at Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing UniversityNanjingJiangsuP. R. China
| | - Qilei Xin
- Jinan Microecological Biomedicine Shandong LaboratoryJinanShandongP. R. China
| | - Xiaosong Gu
- State Key Laboratory of Pharmaceutical BiotechnologyNational Institute of Healthcare Data Science at Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing UniversityNanjingJiangsuP. R. China
- Jinan Microecological Biomedicine Shandong LaboratoryJinanShandongP. R. China
| | - Chunping Jiang
- State Key Laboratory of Pharmaceutical BiotechnologyNational Institute of Healthcare Data Science at Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing UniversityNanjingJiangsuP. R. China
- Jinan Microecological Biomedicine Shandong LaboratoryJinanShandongP. R. China
| | - Junhua Wu
- State Key Laboratory of Pharmaceutical BiotechnologyNational Institute of Healthcare Data Science at Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing UniversityNanjingJiangsuP. R. China
- Jinan Microecological Biomedicine Shandong LaboratoryJinanShandongP. R. China
| |
Collapse
|
|
7
|
Silveira-Freitas JEP, Campagnolo ML, dos Santos Cortez M, de Melo FF, Zarpelon-Schutz AC, Teixeira KN. Long chikungunya? An overview to immunopathology of persistent arthralgia. World J Virol 2024; 13:89985. [PMID: 38984075 PMCID: PMC11229846 DOI: 10.5501/wjv.v13.i2.89985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 02/09/2024] [Accepted: 04/12/2024] [Indexed: 06/24/2024] Open
Abstract
Chikungunya fever (CF) is caused by an arbovirus whose manifestations are extremely diverse, and it has evolved with significant severity in recent years. The clinical signs triggered by the Chikungunya virus are similar to those of other arboviruses. Generally, fever starts abruptly and reaches high levels, followed by severe polyarthralgia and myalgia, as well as an erythematous or petechial maculopapular rash, varying in severity and extent. Around 40% to 60% of affected individuals report persistent arthralgia, which can last from months to years. The symptoms of CF mainly represent the tissue tropism of the virus rather than the immunopathogenesis triggered by the host's immune system. The main mechanisms associated with arthralgia have been linked to an increase in T helper type 17 cells and a consequent increase in receptor activator of nuclear factor kappa-Β ligand and bone resorption. This review suggests that persistent arthralgia results from the presence of viral antigens post-infection and the constant activation of signaling lymphocytic activation molecule family member 7 in synovial macrophages, leading to local infiltration of CD4+ T cells, which sustains the inflammatory process in the joints through the secretion of pro-inflammatory cytokines. The term "long chikungunya" was used in this review to refer to persistent arthralgia since, due to its manifestation over long periods after the end of the viral infection, this clinical condition seems to be characterized more as a sequel than as a symptom, given that there is no active infection involved.
Collapse
Affiliation(s)
| | | | | | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Campus Anísio Teixeira, Vitória da Conquista, Bahia 45029-094, Brazil
| | - Ana Carla Zarpelon-Schutz
- Campus Toledo, Universidade Federal do Paraná, Toledo, Paraná 85919-899, Brazil
- Programa de Pós-graduação em Biotecnologia, Palotina, Universidade Federal do Paraná-Setor Palotina, Paraná 85950-000, Brazil
| | - Kádima Nayara Teixeira
- Campus Toledo, Universidade Federal do Paraná, Toledo, Paraná 85919-899, Brazil
- Programa Multicêntrico de Pós-graduação em Bioquímica e Biologia Molecular, Palotina, Universidade Federal do Paraná-Setor Palotina, Paraná 85950-000, Brazil
| |
Collapse
|
|
8
|
Zhou T, Guan Y, Sun L, Liu W. A review: Mechanisms and molecular pathways of signaling lymphocytic activation molecule family 3 (SLAMF3) in immune modulation and therapeutic prospects. Int Immunopharmacol 2024; 133:112088. [PMID: 38626547 DOI: 10.1016/j.intimp.2024.112088] [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: 01/12/2024] [Revised: 04/10/2024] [Accepted: 04/11/2024] [Indexed: 04/18/2024]
Abstract
The signaling lymphocytic activation molecule (SLAM) family participates in the modulation of various innate and adaptive immune responses. SLAM family (SLAMF) receptors include nine transmembrane glycoproteins, of which SLAMF3 (also known as CD229 or Ly9) has important roles in the modulation of immune responses, from the fundamental activation and suppression of immune cells to the regulation of intricate immune networks. SLAMF3 is mainly expressed in immune cells, such as T, B, and natural killer cells. It has a unique molecular structure, including four immunoglobulin-like domains in the extracellular domain and two immunoreceptor tyrosine-based signaling motifs in the intracellular structural domains. These unique structures have important implications for protein functioning. SLAMF3 is involved in pathogenesis of various disease, particularly autoimmune diseases and cancer. However, despite its potential clinical significance, a comprehensive overview of the current paradigm of SLAMF3 research is lacking. This review summarizes the structure, functional mechanisms, and therapeutic implications of SLAMF3. Our findings highlight the significance of SLAMF3 in both physiological and pathological contexts, and underline its dual role in autoimmunity and malignancies, and including disease progression and prognosis. The review also proposes that future studies on SLAMF3 should explore its context-specific inhibitory and stimulatory effects, expand on its potential in disease mapping, investigate related signaling pathways, and explore its value as a drug target. Research in these areas related to SLAMF3 can provide more precise directions for future therapeutic strategies.
Collapse
Affiliation(s)
- Tong Zhou
- Department of Endocrinology and Metabolism, the First Hospital of Jilin University, Changchun 130021, China; Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun 130021, China; National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun 130021, China
| | - Yanjie Guan
- Department of Oncology, the First Hospital of Jilin University, Changchun 130021, China
| | - Lin Sun
- Department of Endocrinology and Metabolism, the First Hospital of Jilin University, Changchun 130021, China
| | - Wentao Liu
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun 130021, China; National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun 130021, China.
| |
Collapse
|
|
9
|
Kľoc D, Kurhajec S, Huniadi M, Sýkora J, Guman T, Šarišský M. SLAM Family Receptors in B Cell Chronic Lymphoproliferative Disorders. Int J Mol Sci 2024; 25:4014. [PMID: 38612827 PMCID: PMC11012012 DOI: 10.3390/ijms25074014] [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: 02/20/2024] [Revised: 03/28/2024] [Accepted: 03/31/2024] [Indexed: 04/14/2024] Open
Abstract
The signaling lymphocytic activation molecule (SLAM) receptor family (SLAMF) consists of nine glycoproteins that belong to the CD2 superfamily of immunoglobulin (Ig) domain-containing molecules. SLAMF receptors modulate the differentiation and activation of a wide range of immune cells. Individual SLAMF receptors are expressed on the surface of hematopoietic stem cells, hematopoietic progenitor cells, B cells, T cells, NK cells, NKT cells, monocytes, macrophages, dendritic cells, neutrophils, and platelets. The expression of SLAMF receptors was studied during normal B cell maturation. Several SLAMF receptors were also detected in cancer cell lines of B-lymphoid origin and in pathological B cells from patients with B cell chronic lymphoproliferative disorders (B-CLPD), the most frequent hematological malignancies in adults. This review summarizes current knowledge on the expression of SLAMF receptors and their adaptor proteins SAP and EAT-2 in B-CLPD. Several SLAMF receptors could be regarded as potential diagnostic and differential diagnostic markers, prognostic factors, and targets for the development of novel drugs for patients with B-CLPD.
Collapse
Affiliation(s)
- Dominik Kľoc
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, Trieda SNP 1, 04011 Košice, Slovakia; (D.K.); (M.H.)
| | - Slavomír Kurhajec
- Department of Pharmaceutical Technology, Pharmacognosy, and Botany, University of Veterinary Medicine and Pharmacy, Komenského 73, 04181 Košice, Slovakia;
| | - Mykhailo Huniadi
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, Trieda SNP 1, 04011 Košice, Slovakia; (D.K.); (M.H.)
| | - Ján Sýkora
- Department of Haematology and Oncohaematology, Faculty of Medicine, Pavol Jozef Šafárik University in Košice and Louis Pasteur University Hospital Košice, Trieda SNP 1, 04011 Košice, Slovakia; (J.S.); (T.G.)
| | - Tomáš Guman
- Department of Haematology and Oncohaematology, Faculty of Medicine, Pavol Jozef Šafárik University in Košice and Louis Pasteur University Hospital Košice, Trieda SNP 1, 04011 Košice, Slovakia; (J.S.); (T.G.)
| | - Marek Šarišský
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, Trieda SNP 1, 04011 Košice, Slovakia; (D.K.); (M.H.)
| |
Collapse
|
|
10
|
Li R, Galindo CC, Davidson D, Guo H, Zhong MC, Qian J, Li B, Ruzsics Z, Lau CM, O'Sullivan TE, Vidal SM, Sun JC, Veillette A. Suppression of adaptive NK cell expansion by macrophage-mediated phagocytosis inhibited by 2B4-CD48. Cell Rep 2024; 43:113800. [PMID: 38386559 DOI: 10.1016/j.celrep.2024.113800] [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: 06/30/2023] [Revised: 12/21/2023] [Accepted: 01/31/2024] [Indexed: 02/24/2024] Open
Abstract
Infection of mice by mouse cytomegalovirus (MCMV) triggers activation and expansion of Ly49H+ natural killer (NK) cells, which are virus specific and considered to be "adaptive" or "memory" NK cells. Here, we find that signaling lymphocytic activation molecule family receptors (SFRs), a group of hematopoietic cell-restricted receptors, are essential for the expansion of Ly49H+ NK cells after MCMV infection. This activity is largely mediated by CD48, an SFR broadly expressed on NK cells and displaying augmented expression after MCMV infection. It is also dependent on the CD48 counter-receptor, 2B4, expressed on host macrophages. The 2B4-CD48 axis promotes expansion of Ly49H+ NK cells by repressing their phagocytosis by virus-activated macrophages through inhibition of the pro-phagocytic integrin lymphocyte function-associated antigen-1 (LFA-1) on macrophages. These data identify key roles of macrophages and the 2B4-CD48 pathway in controlling the expansion of adaptive NK cells following MCMV infection. Stimulation of the 2B4-CD48 axis may be helpful in enhancing adaptive NK cell responses for therapeutic purposes.
Collapse
Affiliation(s)
- Rui Li
- Laboratory of Molecular Oncology, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Department of Medicine, McGill University, Montréal, QC H3G 1Y6, Canada
| | - Cristian Camilo Galindo
- Laboratory of Molecular Oncology, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Department of Medicine, McGill University, Montréal, QC H3G 1Y6, Canada
| | - Dominique Davidson
- Laboratory of Molecular Oncology, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada
| | - Huaijian Guo
- Laboratory of Molecular Oncology, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Department of Medicine, McGill University, Montréal, QC H3G 1Y6, Canada
| | - Ming-Chao Zhong
- Laboratory of Molecular Oncology, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada
| | - Jin Qian
- Laboratory of Molecular Oncology, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada
| | - Bin Li
- Laboratory of Molecular Oncology, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Molecular Biology Program, University of Montréal, Montréal, QC H3T 1J4, Canada
| | - Zsolt Ruzsics
- Institute of Virology, University Medical Center, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
| | - Colleen M Lau
- Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
| | - Timothy E O'Sullivan
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Silvia M Vidal
- Department of Human Genetics, McGill University, Montréal, QC H3A 0C7, Canada; Dahdaleh Institute of Genomic Medicine, McGill University, Montréal, QC H3A 0G1, Canada
| | - Joseph C Sun
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10065, USA
| | - André Veillette
- Laboratory of Molecular Oncology, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Department of Medicine, McGill University, Montréal, QC H3G 1Y6, Canada; Molecular Biology Program, University of Montréal, Montréal, QC H3T 1J4, Canada.
| |
Collapse
|
|
11
|
Nersesian S, Carter EB, Lee SN, Westhaver LP, Boudreau JE. Killer instincts: natural killer cells as multifactorial cancer immunotherapy. Front Immunol 2023; 14:1269614. [PMID: 38090565 PMCID: PMC10715270 DOI: 10.3389/fimmu.2023.1269614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Accepted: 10/30/2023] [Indexed: 12/18/2023] Open
Abstract
Natural killer (NK) cells integrate heterogeneous signals for activation and inhibition using germline-encoded receptors. These receptors are stochastically co-expressed, and their concurrent engagement and signaling can adjust the sensitivity of individual cells to putative targets. Against cancers, which mutate and evolve under therapeutic and immunologic pressure, the diversity for recognition provided by NK cells may be key to comprehensive cancer control. NK cells are already being trialled as adoptive cell therapy and targets for immunotherapeutic agents. However, strategies to leverage their naturally occurring diversity and agility have not yet been developed. In this review, we discuss the receptors and signaling pathways through which signals for activation or inhibition are generated in NK cells, focusing on their roles in cancer and potential as targets for immunotherapies. Finally, we consider the impacts of receptor co-expression and the potential to engage multiple pathways of NK cell reactivity to maximize the scope and strength of antitumor activities.
Collapse
Affiliation(s)
- Sarah Nersesian
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
- Beatrice Hunter Cancer Research Institute, Halifax, NS, Canada
| | - Emily B. Carter
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
- Beatrice Hunter Cancer Research Institute, Halifax, NS, Canada
| | - Stacey N. Lee
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
- Beatrice Hunter Cancer Research Institute, Halifax, NS, Canada
| | | | - Jeanette E. Boudreau
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
- Beatrice Hunter Cancer Research Institute, Halifax, NS, Canada
- Department of Pathology, Dalhousie University, Halifax, NS, Canada
| |
Collapse
|
|
12
|
Liu J, Peng H, Yu T, Huang Y, Tan N, Pang L, Wu Y, Wang L. Increased SLAMF7 +CD8 + T cells are associated with the pathogenesis of experimental autoimmune pancreatitis in mice. Pancreatology 2023; 23:767-776. [PMID: 37661465 DOI: 10.1016/j.pan.2023.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 08/16/2023] [Accepted: 08/20/2023] [Indexed: 09/05/2023]
Abstract
BACKGROUND IgG4-related autoimmune pancreatitis (AIP) is considered to be a T cell-mediated autoimmune disease. However, CD8+ T cells have only received brief mention, and have yet to be completely studied. The study aimed to investigate the expression of signaling lymphocytic activation molecule family 7 (SLAMF7) on CD8+ T cells and the features of SLAMF7+CD8+ T cells in MRL/Mp mice with AIP. METHODS A murine model of AIP was established by intraperitoneal injection with polyinosinic:polycytidylic acid (poly I:C) for 8 weeks. Dexamethasone treatment was daily administrated for the last 2 weeks during a 6-week course of poly I:C. SLAMF7 expression on CD8+ T cells in the spleen and pancreas was detected by flow cytometry. Granzyme B (GZMB) and cytokines including IFN-γ, TNF-α, and IL-2, were monitored in an in vitro T cell activation assay. Dexamethasone suppression assays were performed to downregulate SLAMF7 expression on T cells upon T cell receptor stimulation. RESULTS AIP in MRL/Mp mice was induced by repeated intraperitoneal administration of poly I:C and CD8+ T cells were increased in the inflamed pancreas. SLAMF7+CD8+ T cells were elevated in the spleen and pancreas of AIP mice. SLAMF7+CD8+ T subsets produced more GZMB, IFN-γ, TNF-α and IL-2 than SLAMF7-CD8+ T subsets. Dexamethasone treatment ameliorated pancreatic inflammatory and fibrosis of AIP. Dexamethasone could downregulate SLAMF7+CD8+ T cells and reduce GZMB, IFN-γ and TNF-α levels both in vitro and in vivo. CONCLUSIONS Increased SLAMF7+CD8+ T cells exhibit enhanced cytotoxicity and cytokines secretion capacity, which may be involved in the pathogenesis of AIP.
Collapse
Affiliation(s)
- Jia Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Hui Peng
- Department of Pathology, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Tingfeng Yu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yanlin Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Ning Tan
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Li Pang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yongtong Wu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Lingyun Wang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
| |
Collapse
|
|
13
|
Choe U, Pham Q, Kim YS, Yu L, Wang TTY. Identification and elucidation of cross talk between SLAM Family Member 7 (SLAMF7) and Toll-like receptor (TLR) pathways in monocytes and macrophages. Sci Rep 2023; 13:11007. [PMID: 37420084 PMCID: PMC10329007 DOI: 10.1038/s41598-023-37040-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 06/14/2023] [Indexed: 07/09/2023] Open
Abstract
To further elucidate the expression, regulation and function of Signaling Lymphocytic Activation Molecule Family (SLAMF) protein members in human monocytes and macrophages. Un-differentiated monocytic THP-1 cell (u-THP-1) and differentiated THP-1 macrophage (d-THP-1) were used as culture models in the study. Responses of cells to the differentiation agents phorbol ester (25 ng/ml) and TLR (Toll-like receptor) ligands were assessed. RT-PCR and Western blot analysis were used to determine mRNA and protein level. Pro-inflammatory cytokine mRNA expression levels and phagocytosis were used as functional markers. Data analyzed using t-test, one-way or two-way ANOVA followed by post hoc test. SLAMFs were differentially expressed in THP-1 cells. Differentiation of u-THP-1 to d-THP-1 led to significantly higher SLAMF7 mRNA and protein levels than other SLAMF. In addition, TLR stimuli increased SLAMF7 mRNA expression but not protein expression. Importantly, SLAMF7 agonist antibody and TLR ligands synergistically increased the mRNA expression levels of IL-1β, IL-6 and TNF-α, but had no effect on phagocytosis. SLAMF7 knocked-down in d-THP-1 significantly lowered TLR-induced mRNA expressions of pro-inflammatory markers. SLAM family proteins are differentially regulated by differentiation and TLRs. SLAMF7 enhanced TLR-mediated induction of pro-inflammatory cytokines in monocytes and macrophages but not phagocytosis.
Collapse
Affiliation(s)
- Uyory Choe
- Department of Nutrition and Food Science, University of Maryland, College Park, MD, 20742, USA
| | - Quynhchi Pham
- U.S. Department of Agriculture, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet, Genomics and Immunology Laboratory, Beltsville, MD, 20705, USA
| | - Young S Kim
- Cancer Prevention Science Branch, Division of Cancer Prevention, NCI, Rockville, MD, 20850, USA
| | - Liangli Yu
- Department of Nutrition and Food Science, University of Maryland, College Park, MD, 20742, USA
| | - Thomas T Y Wang
- U.S. Department of Agriculture, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet, Genomics and Immunology Laboratory, Beltsville, MD, 20705, USA.
| |
Collapse
|
|
14
|
Shah R, van den Berk PCM, Pritchard CEJ, Song JY, Kreft M, Pilzecker B, Jacobs H. A C57BL/6J Fancg-KO Mouse Model Generated by CRISPR/Cas9 Partially Captures the Human Phenotype. Int J Mol Sci 2023; 24:11129. [PMID: 37446306 DOI: 10.3390/ijms241311129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/03/2023] [Accepted: 07/04/2023] [Indexed: 07/15/2023] Open
Abstract
Fanconi anemia (FA) develops due to a mutation in one of the FANC genes that are involved in the repair of interstrand crosslinks (ICLs). FANCG, a member of the FA core complex, is essential for ICL repair. Previous FANCG-deficient mouse models were generated with drug-based selection cassettes in mixed mice backgrounds, leading to a disparity in the interpretation of genotype-related phenotype. We created a Fancg-KO (KO) mouse model using CRISPR/Cas9 to exclude these confounders. The entire Fancg locus was targeted and maintained on the immunological well-characterized C57BL/6J background. The intercrossing of heterozygous mice resulted in sub-Mendelian numbers of homozygous mice, suggesting the loss of FANCG can be embryonically lethal. KO mice displayed infertility and hypogonadism, but no other developmental problems. Bone marrow analysis revealed a defect in various hematopoietic stem and progenitor subsets with a bias towards myelopoiesis. Cell lines derived from Fancg-KO mice were hypersensitive to the crosslinking agents cisplatin and Mitomycin C, and Fancg-KO mouse embryonic fibroblasts (MEFs) displayed increased γ-H2AX upon cisplatin treatment. The reconstitution of these MEFs with Fancg cDNA corrected for the ICL hypersensitivity. This project provides a new, genetically, and immunologically well-defined Fancg-KO mouse model for further in vivo and in vitro studies on FANCG and ICL repair.
Collapse
Affiliation(s)
- Ronak Shah
- Department of Tumor Biology and Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
| | - Paul C M van den Berk
- Department of Tumor Biology and Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
| | - Colin E J Pritchard
- Mouse Clinic for Cancer and Aging Transgenic Facility, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
| | - Ji-Ying Song
- Department of Experimental Animal Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
| | - Maaike Kreft
- Department of Tumor Biology and Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
| | - Bas Pilzecker
- Department of Tumor Biology and Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
| | - Heinz Jacobs
- Department of Tumor Biology and Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
| |
Collapse
|
|
15
|
Farhangnia P, Ghomi SM, Mollazadehghomi S, Nickho H, Akbarpour M, Delbandi AA. SLAM-family receptors come of age as a potential molecular target in cancer immunotherapy. Front Immunol 2023; 14:1174138. [PMID: 37251372 PMCID: PMC10213746 DOI: 10.3389/fimmu.2023.1174138] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 05/02/2023] [Indexed: 05/31/2023] Open
Abstract
The signaling lymphocytic activation molecule (SLAM) family receptors were discovered in immune cells for the first time. The SLAM-family receptors are a significant player in cytotoxicity, humoral immune responses, autoimmune diseases, lymphocyte development, cell survival, and cell adhesion. There is growing evidence that SLAM-family receptors have been involved in cancer progression and heralded as a novel immune checkpoint on T cells. Previous studies have reported the role of SLAMs in tumor immunity in various cancers, including chronic lymphocytic leukemia, lymphoma, multiple myeloma, acute myeloid leukemia, hepatocellular carcinoma, head and neck squamous cell carcinoma, pancreas, lung, and melanoma. Evidence has deciphered that the SLAM-family receptors may be targeted for cancer immunotherapy. However, our understanding in this regard is not complete. This review will discuss the role of SLAM-family receptors in cancer immunotherapy. It will also provide an update on recent advances in SLAM-based targeted immunotherapies.
Collapse
Affiliation(s)
- Pooya Farhangnia
- Immunology Research Center, Institute of Immunology and Infectious Disease, Iran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Board for Transplantation and Cell-Based Therapeutics (ImmunoTACT), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Shamim Mollazadeh Ghomi
- Immunology Board for Transplantation and Cell-Based Therapeutics (ImmunoTACT), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Shabnam Mollazadehghomi
- Immunology Board for Transplantation and Cell-Based Therapeutics (ImmunoTACT), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Hamid Nickho
- Immunology Research Center, Institute of Immunology and Infectious Disease, Iran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mahzad Akbarpour
- Immunology Board for Transplantation and Cell-Based Therapeutics (ImmunoTACT), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Advanced Cellular Therapeutics Facility (ACTF), Hematopoietic Cellular Therapy Program, Section of Hematology & Oncology, Department of Medicine, University of Chicago Medical Center, Chicago, IL, United States
| | - Ali-Akbar Delbandi
- Immunology Research Center, Institute of Immunology and Infectious Disease, Iran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
16
|
Gradauskaite V, Inglebert M, Doench J, Scherer M, Dettwiler M, Wyss M, Shrestha N, Rottenberg S, Plattet P. LRP6 Is a Functional Receptor for Attenuated Canine Distemper Virus. mBio 2023; 14:e0311422. [PMID: 36645301 PMCID: PMC9973313 DOI: 10.1128/mbio.03114-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 12/06/2022] [Indexed: 01/17/2023] Open
Abstract
Wild-type canine distemper virus (CDV) is an important pathogen of dogs as well as wildlife that can infect immune and epithelial cells through two known receptors: the signaling lymphocytic activation molecule (SLAM) and nectin-4, respectively. Conversely, the ferret and egg-adapted CDV-Onderstepoort strain (CDV-OP) is employed as an effective vaccine for dogs. CDV-OP also exhibits promising oncolytic properties, such as its abilities to infect and kill multiple cancer cells in vitro. Interestingly, several cancer cells do not express SLAM or nectin-4, suggesting the presence of a yet unknown entry factor for CDV-OP. By conducting a genome-wide CRISPR/Cas9 knockout (KO) screen in CDV-OP-susceptible canine mammary carcinoma P114 cells, which neither express SLAM nor nectin-4, we identified low-density lipoprotein receptor-related protein 6 (LRP6) as a host factor that promotes CDV-OP infectivity. Whereas the genetic ablation of LRP6 rendered cells resistant to infection, ectopic expression in resistant LRP6KO cells restored susceptibility. Furthermore, multiple functional studies revealed that (i) the overexpression of LRP6 leads to increased cell-cell fusion, (ii) a soluble construct of the viral receptor-binding protein (solHOP) interacts with a soluble form of LRP6 (solLRP6), (iii) an H-OP point mutant that prevents interaction with solLRP6 abrogates cell entry in multiple cell lines once transferred into recombinant viral particles, and (iv) vesicular stomatitis virus (VSV) pseudotyped with CDV-OP envelope glycoproteins loses its infectivity in LRP6KO cells. Collectively, our study identified LRP6 as the long sought-after cell entry receptor of CDV-OP in multiple cell lines, which set the molecular bases to refine our understanding of viral-cell adaptation and to further investigate its oncolytic properties. IMPORTANCE Oncolytic viruses (OV) have gathered increasing interest in recent years as an alternative option to treat cancers. The Onderstepoort strain of canine distemper virus (CDV-OP), an enveloped RNA virus belonging to the genus Morbillivirus, is employed as a safe and efficient vaccine for dogs against distemper disease. Importantly, although CDV-OP can infect and kill multiple cancer cell lines, the basic mechanisms of entry remain to be elucidated, as most of those transformed cells do not express natural receptors (i.e., SLAM and nectin-4). In this study, using a genome-wide CRISPR/Cas9 knockout screen, we describe the discovery of LRP6 as a novel functional entry receptor for CDV-OP in various cancer cell lines and thereby uncover a basic mechanism of cell culture adaptation. Since LRP6 is upregulated in various cancer types, our data provide important insights in order to further investigate the oncolytic properties of CDV-OP.
Collapse
Affiliation(s)
- Vaiva Gradauskaite
- Division of Neurological Sciences, Vetsuisse Faculty, University of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Marine Inglebert
- Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - John Doench
- Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Melanie Scherer
- Division of Neurological Sciences, Vetsuisse Faculty, University of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Martina Dettwiler
- Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Marianne Wyss
- Division of Neurological Sciences, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Neeta Shrestha
- Division of Neurological Sciences, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Sven Rottenberg
- Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
- Bern Center for Precision Medicine, University of Bern, Bern, Switzerland
| | - Philippe Plattet
- Division of Neurological Sciences, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| |
Collapse
|
|
17
|
Ramos-Mejia V, Arellano-Galindo J, Mejía-Arangure JM, Cruz-Munoz ME. A NK Cell Odyssey: From Bench to Therapeutics Against Hematological Malignancies. Front Immunol 2022; 13:803995. [PMID: 35493522 PMCID: PMC9046543 DOI: 10.3389/fimmu.2022.803995] [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: 10/28/2021] [Accepted: 03/11/2022] [Indexed: 11/13/2022] Open
Abstract
In 1975 two independent groups noticed the presence of immune cells with a unique ability to recognize and eliminate transformed hematopoietic cells without any prior sensitization or expansion of specific clones. Since then, NK cells have been the axis of thousands of studies that have resulted until June 2021, in more than 70 000 publications indexed in PubMed. As result of this work, which include approaches in vitro, in vivo, and in natura, it has been possible to appreciate the role played by the NK cells, not only as effectors against specific pathogens, but also as regulators of the immune response. Recent advances have revealed previous unidentified attributes of NK cells including the ability to adapt to new conditions under the context of chronic infections, or their ability to develop some memory-like characteristics. In this review, we will discuss significant findings that have rule our understanding of the NK cell biology, the developing of these findings into new concepts in immunology, and how these conceptual platforms are being used in the design of strategies for cancer immunotherapy.
Collapse
Affiliation(s)
- Veronica Ramos-Mejia
- GENYO: Centro Pfizer, Universidad de Granada, Junta de Andalucía de Genómica e Investigación Oncológica, Granada, Spain
| | - Jose Arellano-Galindo
- Unidad de Investigación en Enfermedades Infecciosas, Hospital Infantil de México “Dr. Federico Gomez”, Ciudad de México, Mexico
| | - Juan Manuel Mejía-Arangure
- Genómica del Cancer, Instituto Nacional de Medicina Genómica (INMEGEN) & Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
- *Correspondence: Mario Ernesto Cruz-Muñoz, ; Juan Manuel Mejía-Arangure,
| | - Mario Ernesto Cruz-Munoz
- Facultad de Medicina, Universidad Autónoma del Estado de Morelos, Cuernavaca, Mexico
- *Correspondence: Mario Ernesto Cruz-Muñoz, ; Juan Manuel Mejía-Arangure,
| |
Collapse
|
|
18
|
Preston SEJ, Emond A, Pettersson F, Dupéré-Richer D, Abraham MJ, Riva A, Kinal M, Rys RN, Johnson NA, Mann KK, del Rincón SV, Licht JD, Miller WH. Acquired Resistance to EZH2 Inhibitor GSK343 Promotes the Differentiation of Human DLBCL Cell Lines toward an ABC-Like Phenotype. Mol Cancer Ther 2022; 21:511-521. [PMID: 35086959 PMCID: PMC8983450 DOI: 10.1158/1535-7163.mct-21-0216] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 10/30/2021] [Accepted: 01/25/2022] [Indexed: 11/16/2022]
Abstract
Diffuse large B-cell lymphoma (DLBCL) accounts for 40% of non-Hodgkin lymphoma, and 30% to 40% of patients will succumb to relapsed/refractory disease (rrDLBCL). Patients with rrDLBCL generally have low long-term survival rates due to a lack of efficient salvage therapies. Small-molecule inhibitors targeting the histone methyltransferase EZH2 represent an emerging group of novel therapeutics that show promising clinical efficacy in patients with rrDLBCL. The mechanisms that control acquired resistance to this class of targeted therapies, however, remain poorly understood. Here, we develop a model of resistance to the EZH2 inhibitor (EZH2i) GSK343 and use RNA-seq data and in vitro investigation to show that GCB (germinal center B-cell)-DLBCL cell lines with acquired drug resistance differentiate toward an ABC (activated B-cell)-DLBCL phenotype. We further observe that the development of resistance to GSK343 is sufficient to induce cross-resistance to other EZH2i. Notably, we identify the immune receptor SLAMF7 as upregulated in EZH2i-resistant cells, using chromatin immunoprecipitation profiling to uncover the changes in chromatin landscape remodeling that permit this altered gene expression. Collectively, our data reveal a previously unreported response to the development of EZH2i resistance in DLBCL, while providing strong rationale for pursuing investigation of dual-targeting of EZH2 and SLAMF7 in rrDLBCL.
Collapse
Affiliation(s)
- Samuel E J Preston
- Division of Experimental Medicine, McGill University, Montréal, Québec, Canada
- Lady Davis Institute for Medical Research, McGill University, Montréal, Québec, Canada
| | - Audrey Emond
- Lady Davis Institute for Medical Research, McGill University, Montréal, Québec, Canada
| | - Filippa Pettersson
- Lady Davis Institute for Medical Research, McGill University, Montréal, Québec, Canada
| | - Daphné Dupéré-Richer
- Division of Experimental Medicine, McGill University, Montréal, Québec, Canada
- Lady Davis Institute for Medical Research, McGill University, Montréal, Québec, Canada
- University of Florida Health Cancer Centre, Florida, USA
| | - Madelyn Jean Abraham
- Division of Experimental Medicine, McGill University, Montréal, Québec, Canada
- Lady Davis Institute for Medical Research, McGill University, Montréal, Québec, Canada
| | - Alberto Riva
- Interdisciplinary Center for Biotechnology Research, University of Florida, Florida, USA
| | - Mena Kinal
- Lady Davis Institute for Medical Research, McGill University, Montréal, Québec, Canada
| | - Ryan N Rys
- Lady Davis Institute for Medical Research, McGill University, Montréal, Québec, Canada
| | - Nathalie A Johnson
- Lady Davis Institute for Medical Research, McGill University, Montréal, Québec, Canada
- Department of Medicine, McGill University, Montréal, Québec, Canada
- Departments of Medicine and Oncology, Jewish General Hospital, Montréal, Québec, Canada
| | - Koren K Mann
- Division of Experimental Medicine, McGill University, Montréal, Québec, Canada
- Lady Davis Institute for Medical Research, McGill University, Montréal, Québec, Canada
- Department of Medicine, McGill University, Montréal, Québec, Canada
| | - Sonia V del Rincón
- Division of Experimental Medicine, McGill University, Montréal, Québec, Canada
- Lady Davis Institute for Medical Research, McGill University, Montréal, Québec, Canada
- Department of Medicine, McGill University, Montréal, Québec, Canada
- Department of Oncology, McGill University, Montréal, Québec, Canada
| | | | - Wilson H Miller
- Division of Experimental Medicine, McGill University, Montréal, Québec, Canada
- Lady Davis Institute for Medical Research, McGill University, Montréal, Québec, Canada
- Department of Medicine, McGill University, Montréal, Québec, Canada
- Departments of Medicine and Oncology, Jewish General Hospital, Montréal, Québec, Canada
- Department of Oncology, McGill University, Montréal, Québec, Canada
| |
Collapse
|
|
19
|
Whole-genome profiling of DNA methylation and hydroxymethylation identifies distinct regulatory programs among innate lymphocytes. Nat Immunol 2022; 23:619-631. [PMID: 35332328 PMCID: PMC8989654 DOI: 10.1038/s41590-022-01164-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 02/18/2022] [Indexed: 12/11/2022]
Abstract
Innate lymphocytes encompass a diverse array of phenotypic identities with specialized functions. DNA methylation and hydroxymethylation are essential for epigenetic fidelity and fate commitment. The landscapes of these modifications are unknown in innate lymphocytes. Here, we characterized the whole-genome distribution of methyl-CpG and 5-hydroxymethylcytosine in mouse ILC3, ILC2, and NK cells. We identified differentially methylated and hydroxymethylated DNA regions between ILC-NK subsets and correlated them with transcriptional signatures. We associated lineage-determining transcription factors with demethylation and demonstrated unique patterns of DNA methylation/hydroxymethylation in relationship to open chromatin regions, histone modifications, and transcription factor binding sites. We further discovered a novel association between hydroxymethylation and NK cell super-enhancers. Using mice lacking DNA hydroxymethylase TET2, we showed its requirement for optimal production of hallmark cytokines by ILC3 and IL-17A by inflammatory ILC2. These findings provide a powerful resource for studying innate lymphocyte epigenetic regulation and decode the regulatory logic governing their identity.
Collapse
|
|
20
|
Simmons DP, Nguyen HN, Gomez-Rivas E, Jeong Y, Jonsson AH, Chen AF, Lange JK, Dyer GS, Blazar P, Earp BE, Coblyn JS, Massarotti EM, Sparks JA, Todd DJ, Accelerating Medicines Partnership ® (AMP ®) RA/SLE Network, Rao DA, Kim EY, Brenner MB. SLAMF7 engagement superactivates macrophages in acute and chronic inflammation. Sci Immunol 2022; 7:eabf2846. [PMID: 35148199 PMCID: PMC8991457 DOI: 10.1126/sciimmunol.abf2846] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Macrophages regulate protective immune responses to infectious microbes, but aberrant macrophage activation frequently drives pathological inflammation. To identify regulators of vigorous macrophage activation, we analyzed RNA-seq data from synovial macrophages and identified SLAMF7 as a receptor associated with a superactivated macrophage state in rheumatoid arthritis. We implicated IFN-γ as a key regulator of SLAMF7 expression and engaging SLAMF7 drove a strong wave of inflammatory cytokine expression. Induction of TNF-α after SLAMF7 engagement amplified inflammation through an autocrine signaling loop. We observed SLAMF7-induced gene programs not only in macrophages from rheumatoid arthritis patients but also in gut macrophages from patients with active Crohn's disease and in lung macrophages from patients with severe COVID-19. This suggests a central role for SLAMF7 in macrophage superactivation with broad implications in human disease pathology.
Collapse
Affiliation(s)
- Daimon P. Simmons
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA
- Harvard Medical School, Boston, MA
| | - Hung N. Nguyen
- Harvard Medical School, Boston, MA
- Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - Emma Gomez-Rivas
- Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - Yunju Jeong
- Harvard Medical School, Boston, MA
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - A. Helena Jonsson
- Harvard Medical School, Boston, MA
- Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - Antonia F. Chen
- Harvard Medical School, Boston, MA
- Department of Orthopedic Surgery, Brigham and Women’s Hospital, Boston, MA
| | - Jeffrey K. Lange
- Harvard Medical School, Boston, MA
- Department of Orthopedic Surgery, Brigham and Women’s Hospital, Boston, MA
| | - George S. Dyer
- Harvard Medical School, Boston, MA
- Department of Orthopedic Surgery, Brigham and Women’s Hospital, Boston, MA
| | - Philip Blazar
- Harvard Medical School, Boston, MA
- Department of Orthopedic Surgery, Brigham and Women’s Hospital, Boston, MA
| | - Brandon E. Earp
- Harvard Medical School, Boston, MA
- Department of Orthopedic Surgery, Brigham and Women’s Hospital, Boston, MA
| | - Jonathan S. Coblyn
- Harvard Medical School, Boston, MA
- Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - Elena M. Massarotti
- Harvard Medical School, Boston, MA
- Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - Jeffrey A. Sparks
- Harvard Medical School, Boston, MA
- Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - Derrick J. Todd
- Harvard Medical School, Boston, MA
- Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | | | - Deepak A. Rao
- Harvard Medical School, Boston, MA
- Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - Edy Y. Kim
- Harvard Medical School, Boston, MA
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - Michael B. Brenner
- Harvard Medical School, Boston, MA
- Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| |
Collapse
|
|
21
|
Development of αβ T Cells with Innate Functions. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1365:149-160. [DOI: 10.1007/978-981-16-8387-9_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
|
|
22
|
Immunogenetics of Lupus Erythematosus. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1367:213-257. [DOI: 10.1007/978-3-030-92616-8_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
|
|
23
|
CD48-expressing non-small-cell lung cancer cells are susceptible to natural killer cell-mediated cytotoxicity. Arch Pharm Res 2021; 45:1-10. [PMID: 34905179 DOI: 10.1007/s12272-021-01365-z] [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: 10/13/2021] [Accepted: 12/07/2021] [Indexed: 01/21/2023]
Abstract
The susceptibility of cancer cells to natural killer (NK) cell-mediated cytotoxicity depends on the balance of activating and inhibitory ligands expressed on their surface. Although many types of cancer cells are killed by NK cells, non-small-cell lung cancer (NSCLC) cells are relatively resistant to NK cell-mediated cytotoxicity. In this study, we showed that several NSCLC cell lines have differential sensitivity to NK cell-mediated cytotoxicity: NCI-H522 cells were highly sensitive, but A549, NCI-H23, NCI-H1915, and NCI-H1299 were resistant. Among activating ligands such as CD48, HLA-A/B/G, ICAM-1, MICA/B, and ULBPs, only CD48 rendered NCI-H522 cells susceptible to NK cell-mediated cytotoxicity, which was proved by using CD48 siRNA and neutralizing antibody. CD48-positive NCI-H522 cells established a more stable contact with NK cells than did CD48-negative A549 and CD48 siRNA cell-transfected NCI-H522 cells. Taken together, these data demonstrate that CD48-positive NSCLC cells might be susceptible to NK cell-mediated cytotoxicity, which provide information on how to stratify NSCLC patients potentially responsive to NK-cell therapy.
Collapse
|
|
24
|
Tang Z, Davidson D, Li R, Zhong MC, Qian J, Chen J, Veillette A. Inflammatory macrophages exploit unconventional pro-phagocytic integrins for phagocytosis and anti-tumor immunity. Cell Rep 2021; 37:110111. [PMID: 34910922 DOI: 10.1016/j.celrep.2021.110111] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 10/14/2021] [Accepted: 11/18/2021] [Indexed: 11/19/2022] Open
Abstract
Blockade of the inhibitory checkpoint SIRPα-CD47 promotes phagocytosis of cancer cells by macrophages and is a promising avenue in anti-cancer therapy. Productive phagocytosis is strictly predicated on co-engagement of pro-phagocytic receptors-namely, Fc receptors (FcRs), integrin CD11b, or SLAMF7-by their ligands on cancer cells. Here, we examine whether additional pro-phagocytic receptors could be harnessed to broaden the scope of phagocytosis. Inflammatory stimuli, including multiple cytokines and Toll-like receptor (TLR) ligands, augment phagocytosis efficiency and fully alleviate the requirement of FcRs, CD11b, and SLAMF7 for phagocytosis. These effects are mediated by the unconventional pro-phagocytic integrins CD11a and CD11c, which act with CD18 to initiate actin polarization, leading to phagocytosis. Some inflammatory stimuli enable phagocytosis even in the absence of SIRPα-CD47 blockade. Higher CD11c expression in macrophage-enriched tumors correlates with improved survival in clinical studies. Thus, inflammatory macrophages exploit unconventional pro-phagocytic integrins for improved phagocytosis and anti-tumor immunity.
Collapse
Affiliation(s)
- Zhenghai Tang
- Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada
| | - Dominique Davidson
- Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada
| | - Rui Li
- Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Department of Medicine, McGill University, Montréal, QC H3G 1Y6, Canada
| | - Ming-Chao Zhong
- Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada
| | - Jin Qian
- Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada
| | - Jun Chen
- Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.
| | - André Veillette
- Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Department of Medicine, McGill University, Montréal, QC H3G 1Y6, Canada; Department of Medicine, University of Montréal, Montréal, QC H3C 3J7, Canada.
| |
Collapse
|
|
25
|
Gutierrez-Guerrero A, Mancilla-Herrera I, Maravillas-Montero JL, Martinez-Duncker I, Veillette A, Cruz-Munoz ME. SLAMF7 selectively favors degranulation to promote cytotoxicity in human NK cells. Eur J Immunol 2021; 52:62-74. [PMID: 34693521 DOI: 10.1002/eji.202149406] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 09/01/2021] [Accepted: 10/20/2021] [Indexed: 01/08/2023]
Abstract
NK cells play an important role in immunity by recognizing and eliminating cells undergoing infection or malignant transformation. This role is dependent on the ability of NK cells to lyse targets cells in a perforin-dependent mechanism and by secreting inflammatory cytokines. Both effector functions are controlled by several cell surface receptors. The Signaling Lymphocyte Activation Molecule (SLAM) family of receptors plays an essential role in regulating NK cell activation. Several studies have demonstrated that SLAMF7 regulates NK cell activation. However, the molecular and cellular mechanisms by which SLAMF7 influences NK effector functions are unknown. Here, we present evidence that physiological ligation of SLAMF7 in human NK cells enhances the lysis of target cells expressing SLAMF7. This effect was dependent on the ability of SLAMF7 to promote NK cell degranulation rather than cytotoxic granule polarization or cell adhesion. Moreover, SLAMF7-dependent NK cell degranulation was predominantly dependent on PLC-γ when compared to PI3K. These data provide novel information on the cellular mechanism by which SLAMF7 regulates human NK cell activation. Finally, this study supports a model for NK cell activation where activated receptors contribute by regulating specific discrete cellular events rather than multiple cellular processes.
Collapse
Affiliation(s)
- Arturo Gutierrez-Guerrero
- Facultad de Medicina, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos, México.,Instituto de Investigación en Ciencias Básicas y Aplicadas, Mexico City, México
| | | | - Jose L Maravillas-Montero
- Red de Apoyo a la Investigación, Universidad Nacional Autónoma de México, Mexico City, México.,Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, México
| | - Ivan Martinez-Duncker
- Centro de Investigación en Dinámica celular, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos, México
| | - Andre Veillette
- Institute de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada
| | - Mario E Cruz-Munoz
- Facultad de Medicina, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos, México
| |
Collapse
|
|
26
|
Abstract
Natural Killer (NK) cells are key effectors of the innate immune system which represent the first line of defense against viral infections. NK cell activation depends on the engagement of a complex receptor repertoire expressed on their surface, consisting of both activating and inhibitory receptors. Among the known NK cell receptors, the family of killer Ig-like receptors (KIRs) consists in activating/inhibitory receptors that interact with specific human leukocyte antigen (HLA) molecules expressed on target cells. In particular, the expression of peculiar KIRs have been reported to be associated to viral infection susceptibility. Interestingly, a significant association between the development and onset of different human pathologies, such as tumors, neurodegeneration and infertility, and a clonal KIRs expression on NK cells has been described in presence of viral infections, supporting the crucial role of KIRs in defining the effect of viral infections in different tissues and organs. This review aims to report the state of art about the role of KIRs receptors in NK cell activation and viral infection control.
Collapse
|
|
27
|
Gartshteyn Y, Askanase AD, Mor A. SLAM Associated Protein Signaling in T Cells: Tilting the Balance Toward Autoimmunity. Front Immunol 2021; 12:654839. [PMID: 33936082 PMCID: PMC8086963 DOI: 10.3389/fimmu.2021.654839] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 03/25/2021] [Indexed: 11/13/2022] Open
Abstract
T cell activation is the result of the integration of signals across the T cell receptor and adjacent co-receptors. The signaling lymphocyte activation molecules (SLAM) family are transmembrane co-receptors that modulate antigen driven T cell responses. Signal transduction downstream of the SLAM receptor is mediated by the adaptor protein SLAM Associated Protein (SAP), a small intracellular protein with a single SH2 binding domain that can recruit tyrosine kinases as well as shield phosphorylated sites from dephosphorylation. Balanced SLAM-SAP signaling within T cells is required for healthy immunity, with deficiency or overexpression prompting autoimmune diseases. Better understanding of the molecular pathways involved in the intracellular signaling downstream of SLAM could provide treatment targets for these autoimmune diseases.
Collapse
Affiliation(s)
- Yevgeniya Gartshteyn
- Division of Rheumatology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, United States
| | - Anca D Askanase
- Division of Rheumatology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, United States
| | - Adam Mor
- Division of Rheumatology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, United States.,Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, United States
| |
Collapse
|
|
28
|
Potential role of diacylglycerol kinases in immune-mediated diseases. Clin Sci (Lond) 2021; 134:1637-1658. [PMID: 32608491 DOI: 10.1042/cs20200389] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 06/08/2020] [Accepted: 06/22/2020] [Indexed: 02/07/2023]
Abstract
The mechanism promoting exacerbated immune responses in allergy and autoimmunity as well as those blunting the immune control of cancer cells are of primary interest in medicine. Diacylglycerol kinases (DGKs) are key modulators of signal transduction, which blunt diacylglycerol (DAG) signals and produce phosphatidic acid (PA). By modulating lipid second messengers, DGK modulate the activity of downstream signaling proteins, vesicle trafficking and membrane shape. The biological role of the DGK α and ζ isoforms in immune cells differentiation and effector function was subjected to in deep investigations. DGK α and ζ resulted in negatively regulating synergistic way basal and receptor induced DAG signals in T cells as well as leukocytes. In this way, they contributed to keep under control the immune response but also downmodulate immune response against tumors. Alteration in DGKα activity is also implicated in the pathogenesis of genetic perturbations of the immune function such as the X-linked lymphoproliferative disease 1 and localized juvenile periodontitis. These findings suggested a participation of DGK to the pathogenetic mechanisms underlying several immune-mediated diseases and prompted several researches aiming to target DGK with pharmacologic and molecular strategies. Those findings are discussed inhere together with experimental applications in tumors as well as in other immune-mediated diseases such as asthma.
Collapse
|
|
29
|
Griffin DE. Measles immunity and immunosuppression. Curr Opin Virol 2021; 46:9-14. [PMID: 32891958 PMCID: PMC7994291 DOI: 10.1016/j.coviro.2020.08.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/04/2020] [Accepted: 08/05/2020] [Indexed: 12/16/2022]
Abstract
Effects of measles on the immune system are only partially understood. Lymphoid tissue is a primary site of measles virus (MeV) replication where CD150 is the receptor for infection of both B and T cells. Lymphocyte depletion occurs during the acute phase of infection, but initiation of the adaptive immune response leads to extensive lymphocyte proliferation, production of MeV-specific antibody and T cells, the rash and clearance of infectious virus. Viral RNA persists in lymphoid tissue accompanied by ongoing germinal center proliferation, production of antibody-secreting cells, functionally distinct populations of T cells and antibody avidity maturation to establish life-long immunity. However, at the same time diversity of pre-existing antibodies and numbers of memory and naive B cells are reduced and susceptibility to other infections is increased.
Collapse
Affiliation(s)
- Diane E Griffin
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
| |
Collapse
|
|
30
|
Immune Functions of Signaling Lymphocytic Activation Molecule Family Molecules in Multiple Myeloma. Cancers (Basel) 2021; 13:cancers13020279. [PMID: 33451089 PMCID: PMC7828503 DOI: 10.3390/cancers13020279] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 01/11/2021] [Accepted: 01/11/2021] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Multiple myeloma (MM) is an incurable hematological malignancy characterized by an increase in abnormal plasma cells. Disease progression, drug resistance, and immunosuppression in MM are associated with immune-related molecules, such as immune checkpoint and co-stimulatory molecules, present in the tumor microenvironment. Novel agents targeting these cell-surface molecules are currently under development, including monoclonal antibodies, bispecific monoclonal antibodies, and chimera antigen receptor T-cell therapies. In this review, we focus on the signaling lymphocytic activation molecule family receptors and provide an overview of their biological functions and novel therapies in MM. Abstract The signaling lymphocytic activation molecule (SLAM) family receptors are expressed on various immune cells and malignant plasma cells in multiple myeloma (MM) patients. In immune cells, most SLAM family molecules bind to themselves to transmit co-stimulatory signals through the recruiting adaptor proteins SLAM-associated protein (SAP) or Ewing’s sarcoma-associated transcript 2 (EAT-2), which target immunoreceptor tyrosine-based switch motifs in the cytoplasmic regions of the receptors. Notably, SLAMF2, SLAMF3, SLAMF6, and SLAMF7 are strongly and constitutively expressed on MM cells that do not express the adaptor proteins SAP and EAT-2. This review summarizes recent studies on the expression and biological functions of SLAM family receptors during the malignant progression of MM and the resulting preclinical and clinical research involving four SLAM family receptors. A better understanding of the relationship between SLAM family receptors and MM disease progression may lead to the development of novel immunotherapies for relapse prevention.
Collapse
|
|
31
|
Shi D, Zhang Y, Tian Y. SLAMF1 Promotes Methotrexate Resistance via Activating Autophagy in Choriocarcinoma Cells. Cancer Manag Res 2020; 12:13427-13436. [PMID: 33408515 PMCID: PMC7779304 DOI: 10.2147/cmar.s278012] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 12/14/2020] [Indexed: 12/28/2022] Open
Abstract
Objective The acquisition of chemoresistance to methotrexate (MTX) still remains one of the major challenges for choriocarcinoma treatment. Herein, we aimed to evaluate the potential role of Signaling Lymphocytic Activation Molecule Family Member 1 (SLAMF1) as a possible regulator of chemoresistance to MTX in choriocarcinoma. Material and Methods MTX-resistant JEG3 and JAR sublines (JEG3/MTX, JAR/MTX) were used to study SLAMF1 function. CCK8 assay and soft agar assay were conducted to measure the cell viability and clonogenesis of choriocarcinoma cells, respectively; MDC incorporation assay was conducted for the quantification of intracellular autophagy; BrdU labeling was used to assess the proliferative potential of choriocarcinoma cells; SLAMF1 protein expression was analyzed by Western blotting. Results Upregulation of SLAMF1 expression was observed in MTX-resistant JEG3/MTX and JAR/MTX sublines compared to their parental JEG3 and JAR cell lines, respectively. Knockdown of SLAMF1 markedly attenuated cell viability and soft agar clonogenesis after incubation with MTX in JEG3/MTX and JAR/MTX cells. In contrast, constitutive expression of SLAMF1 rescued cell survival soft agar clonogenesis in JEG3 and JAR cells treated with MTX. Moreover, autophagy is apparently activated in MTX-resistant JEG3/MTX and JAR/MTX sublines compared to their parental cell lines. Autophagy inhibitor 3-methyladenine and bafilomycin A1 enhanced MTX-induced cytotoxicity in MTX-resistant JEG3 and JAR sublines. Further, SLAMF1 might activate autophagy-related mechanism to promote resistance to MTX in choriocarcinoma cells. Depletion of SLAMF1 suppressed autophagy and induced apoptosis in MTX-treated JEG3/MTX and JAR/MTX cells. Conclusion SLAMF1 might promote MTX resistance via activating protective autophagy in choriocarcinoma cell lines. Targeting SLAMF1 might be a useful therapeutic strategy to sensitize choriocarcinoma cells to MTX-based regimens.
Collapse
Affiliation(s)
- Dazun Shi
- Department of Gynecology and Obstetrics, Xiangya Hospital, Central South University, Changsha, Hunan Province, People's Republic of China
| | - Yu Zhang
- Department of Gynecology and Obstetrics, Xiangya Hospital, Central South University, Changsha, Hunan Province, People's Republic of China
| | - Yan Tian
- Department of Gynecology and Obstetrics, Xiangya Hospital, Central South University, Changsha, Hunan Province, People's Republic of China
| |
Collapse
|
|
32
|
Newhouse DJ, Vernasco BJ. Developing a transcriptomic framework for testing testosterone-mediated handicap hypotheses. Gen Comp Endocrinol 2020; 298:113577. [PMID: 32739436 DOI: 10.1016/j.ygcen.2020.113577] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 07/21/2020] [Accepted: 07/25/2020] [Indexed: 12/17/2022]
Abstract
Sexually selected traits are hypothesized to be honest signals of individual quality due to the costs associated with their maintenance, development, and/or production. Testosterone, a sex steroid associated with the development and/or production of sexually selected traits, has been proposed to enforce the honesty of sexually selected traits via its immunosuppressive effects (i.e., the Immunocompetence Handicap Hypothesis) and/or by influencing an individual's exposure/susceptibility to oxidative stress (i.e., the Oxidation Handicap Hypothesis). Previous work testing these hypotheses has primarily focused on physiological measurements of immunity or oxidative stress, but little is known about the molecular pathways by which testosterone could influence immunity and/or oxidative stress pathways. To further understand the transcriptomic consequences of experimentally elevated testosterone in the context of handicap hypotheses, we used previously published RNA-seq data from studies that measured the transcriptome of individuals treated with either a testosterone-filled or an empty (i.e., control) implant. Two studies encompassing three species of bird and three tissue types fit our selection criteria and we reanalyzed the data using weighted gene co-expression network analysis. Testosterone-treated individuals exhibited signatures of immunosuppression and our results describe the molecular pathways underlying this effect. We also provide some evidence to suggest that the transcriptomic signature of immunosuppression is evolutionarily conserved between the three species. While our results provide no evidence to suggest testosterone mediates handicaps via pathways associated with oxidative stress, they do support the hypothesis that testosterone enforces the honesty of sexually-selected traits by influencing an individual's immunocompetence. Overall, this study develops a framework for testing testosterone-mediated handicap hypotheses and provides guidelines for future integrative and comparative studies focused on the proximate mechanisms mediating sexually selected traits.
Collapse
Affiliation(s)
- Daniel J Newhouse
- Department of Biology, East Carolina University, Greenville, NC, USA.
| | - Ben J Vernasco
- Department of Biological Sciences, Virginia Tech, Blacksburg, VA, USA
| |
Collapse
|
|
33
|
von Wenserski L, Schultheiß C, Bolz S, Schliffke S, Simnica D, Willscher E, Gerull H, Wolters-Eisfeld G, Riecken K, Fehse B, Altfeld M, Nollau P, Binder M. SLAMF receptors negatively regulate B cell receptor signaling in chronic lymphocytic leukemia via recruitment of prohibitin-2. Leukemia 2020; 35:1073-1086. [PMID: 32826957 PMCID: PMC8024197 DOI: 10.1038/s41375-020-01025-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 07/30/2020] [Accepted: 08/07/2020] [Indexed: 01/25/2023]
Abstract
We identified a subset of Chronic Lymphocytic Leukemia (CLL) patients with high Signaling Lymphocytic Activation Molecule Family (SLAMF) receptor-related signaling that showed an indolent clinical course. Since SLAMF receptors play a role in NK cell biology, we reasoned that these receptors may impact NK cell-mediated CLL immunity. Indeed, our experiments showed significantly decreased degranulation capacity of primary NK cells from CLL patients expressing low levels of SLAMF1 and SLAMF7. Since the SLAMFlow signature was strongly associated with an unmutated CLL immunoglobulin heavy chain (IGHV) status in large datasets, we investigated the impact of SLAMF1 and SLAMF7 on the B cell receptor (BCR) signaling axis. Overexpression of SLAMF1 or SLAMF7 in IGHV mutated CLL cell models resulted in reduced proliferation and impaired responses to BCR ligation, whereas the knockout of both receptors showed opposing effects and increased sensitivity toward inhibition of components of the BCR pathway. Detailed molecular analyzes showed that SLAMF1 and SLAMF7 receptors mediate their BCR pathway antagonistic effects via recruitment of prohibitin-2 (PHB2) thereby impairing its role in signal transduction downstream the IGHV-mutant IgM-BCR. Together, our data indicate that SLAMF receptors are important modulators of the BCR signaling axis and may improve immune control in CLL by interference with NK cells.
Collapse
Affiliation(s)
- Lisa von Wenserski
- Department of Internal Medicine IV Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, Halle, Saale, Germany
| | - Christoph Schultheiß
- Department of Internal Medicine IV Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, Halle, Saale, Germany
| | - Sarah Bolz
- TU Dresden, Biotechnologisches Zentrum, Dresden, Germany
| | - Simon Schliffke
- Department of Oncology and Hematology, Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum-University Cancer Center Hamburg, Hamburg, Germany
| | - Donjete Simnica
- Department of Internal Medicine IV Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, Halle, Saale, Germany
| | - Edith Willscher
- Department of Internal Medicine IV Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, Halle, Saale, Germany
| | - Helwe Gerull
- Research Institute Children's Cancer Center and Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Gerrit Wolters-Eisfeld
- Research Institute Children's Cancer Center and Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Kristoffer Riecken
- Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Boris Fehse
- Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marcus Altfeld
- Research Department Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Peter Nollau
- Research Institute Children's Cancer Center and Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Mascha Binder
- Department of Internal Medicine IV Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, Halle, Saale, Germany.
| |
Collapse
|
|
34
|
Ishibashi M, Sunakawa-Kii M, Kaito Y, Kinoshita R, Asayama T, Kuribayashi Y, Inokuchi K, Morita R, Tamura H. The SLAMF3 rs509749 polymorphism correlates with malignant potential in multiple myeloma. Exp Hematol 2020; 90:72-79. [PMID: 32818503 DOI: 10.1016/j.exphem.2020.08.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 08/11/2020] [Accepted: 08/13/2020] [Indexed: 02/06/2023]
Abstract
The signaling lymphocytic activation molecule family 3 (SLAMF3) is highly expressed on plasma cells from patients with multiple myeloma (MM) and induces high malignant potential by ERK signaling mediated via the interaction with adaptor proteins SHP2 and GRB2. This study focused on the single-nucleotide polymorphism (SNP) of the SLAMF3 gene (rs509749, 1804A>G, M602V) in MM. The SNP G allele was a major type, and the frequencies of the GG, GA, and AA genotypes were 61.8%, 29.4%, and 8.8%, respectively, in patients with MM, which was almost the same as in healthy the control group in the Japanese population. Interestingly, patients with GG genotypes had significantly shorter overall survival times than patients with GA/AA genotypes. Consistent with those results, SLAMF3-overexpressing KMS-34 cells with the G allele (V602) had higher cell proliferation potential and were more resistant to anti-MM agents than those with the A allele (M602). When those cells were subcutaneously inoculated into NOG mice, tumor sizes in mice receiving V602 cells rapidly increased, and survival was significantly shorter than in mice injected with M602 cells. Furthermore, SLAMF3 V602 molecules bound more tightly to SHP2 and GRB2, with increased SHP2 and ERK phosphorylation compared with M602 cells. The mRNA expression of cell cycle-related genes (CCND1 and CCNE1) and anti-apoptotic genes (BCL2L and p21) was increased in V602 cells compared with M602 cells. The results thus suggested that the G allele of SLAMF3 SNP rs509749 may be associated with MM disease progression.
Collapse
Affiliation(s)
- Mariko Ishibashi
- Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan
| | | | - Yuta Kaito
- Department of Hematology, Nippon Medical School, Tokyo, Japan
| | | | - Toshio Asayama
- Department of Hematology, Nippon Medical School, Tokyo, Japan
| | | | - Koiti Inokuchi
- Department of Hematology, Nippon Medical School, Tokyo, Japan
| | - Rimpei Morita
- Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan
| | - Hideto Tamura
- Department of Hematology, Nippon Medical School, Tokyo, Japan; Division of Diabetes, Endocrinology and Hematology, Department of Internal Medicine, Dokkyo Medical University Saitama Medical Center, Saitama, Japan.
| |
Collapse
|
|
35
|
Rodríguez-Lobato LG, Ganzetti M, Fernández de Larrea C, Hudecek M, Einsele H, Danhof S. CAR T-Cells in Multiple Myeloma: State of the Art and Future Directions. Front Oncol 2020; 10:1243. [PMID: 32850376 PMCID: PMC7399644 DOI: 10.3389/fonc.2020.01243] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Accepted: 06/16/2020] [Indexed: 01/24/2023] Open
Abstract
Despite recent therapeutic advances, the prognosis of multiple myeloma (MM) patients remains poor. Thus, new strategies to improve outcomes are imperative. Chimeric antigen receptor (CAR) T-cell therapy has changed the treatment landscape of B-cell malignancies, providing a potentially curative option for patients who are refractory to standard treatment. Long-term remissions achieved in patients with acute lymphoblastic leukemia and Non-Hodgkin Lymphoma encouraged its further development in MM. B-cell maturation antigen (BCMA)-targeted CAR T-cells have established outstanding results in heavily pre-treated patients. However, several other antigens such as SLAMF7 and CD44v6 are currently under investigation with promising results. Idecabtagene vicleucel is expected to be approved soon for clinical use. Unfortunately, relapses after CAR T-cell infusion have been reported. Hence, understanding the underlying mechanisms of resistance is essential to promote prevention strategies and to enhance CAR T-cell efficacy. In this review we provide an update of the most recent clinical and pre-clinical data and we elucidate both, the potential and the challenges of CAR T-cell therapy in the future.
Collapse
Affiliation(s)
- Luis Gerardo Rodríguez-Lobato
- Division of Medicine II, University Hospital Würzburg, Würzburg, Germany
- Amyloidosis and Multiple Myeloma Unit, Department of Hematology, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Maya Ganzetti
- Division of Medicine II, University Hospital Würzburg, Würzburg, Germany
- Unit of Hematology and Bone Marrow Transplantation, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Carlos Fernández de Larrea
- Amyloidosis and Multiple Myeloma Unit, Department of Hematology, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Michael Hudecek
- Division of Medicine II, University Hospital Würzburg, Würzburg, Germany
| | - Hermann Einsele
- Division of Medicine II, University Hospital Würzburg, Würzburg, Germany
| | - Sophia Danhof
- Division of Medicine II, University Hospital Würzburg, Würzburg, Germany
| |
Collapse
|
|
36
|
Buller CW, Mathew PA, Mathew SO. Roles of NK Cell Receptors 2B4 (CD244), CS1 (CD319), and LLT1 (CLEC2D) in Cancer. Cancers (Basel) 2020; 12:cancers12071755. [PMID: 32630303 PMCID: PMC7409338 DOI: 10.3390/cancers12071755] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 06/13/2020] [Accepted: 06/26/2020] [Indexed: 12/13/2022] Open
Abstract
Natural killer (NK) cells play a pivotal role in the immune system, especially in the recognition and clearance of cancer cells and infected cells. Their effector function is controlled by a delicate balance between the activating and inhibitory signals. We have identified 2B4 (CD244, SLAMF4) and CS1 (CD319, SLAMF7) as NK cell receptors regulating NK cell cytotoxicity. Lectin-like transcript 1 (LLT1), a member of the C-type lectin-like domain family 2 (CLEC2D), induced IFN-γ production but did not directly regulate cytolytic activity. Interestingly, LLT1 expressed on other cells acts as a ligand for an NK cell inhibitory receptor NKRP1A (CD161) and inhibits NK cytolytic function. Extensive research has been done on novel therapies that target these receptors to increase the effector function of NK cells. The 2B4 receptor is involved in the rejection of melanoma cells in mice. Empliciti, an FDA-approved monoclonal antibody, explicitly targets the CS1 receptor and enhances the NK cell cytotoxicity against multiple myeloma cells. Our studies revealed that LLT1 is expressed on prostate cancer and triple-negative breast cancer cells and allows them to evade NK-cell-mediated killing. In this review, we describe NK cell receptors 2B4, CS1, and LLT1 and their potential in targeting cancer cells for NK-cell-mediated immunotherapy. New cancer immunotherapies like chimeric antigen receptor T (CAR-T) and NK (CAR-NK) cells are showing great promise in the treatment of cancer, and CAR cells specific to these receptors would be an attractive therapeutic option.
Collapse
|
|
37
|
Caraccio C, Krishna S, Phillips DJ, Schürch CM. Bispecific Antibodies for Multiple Myeloma: A Review of Targets, Drugs, Clinical Trials, and Future Directions. Front Immunol 2020; 11:501. [PMID: 32391000 PMCID: PMC7193016 DOI: 10.3389/fimmu.2020.00501] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 03/04/2020] [Indexed: 12/15/2022] Open
Abstract
Multiple myeloma (MM) is a plasma cell malignancy and the second most common hematological neoplasm in adults, comprising 1.8% of all cancers. With an annual incidence of ~30,770 cases in the United States, MM has a high mortality rate, leading to 12,770 deaths per year. MM is a genetically complex, highly heterogeneous malignancy, with significant inter- and intra-patient clonal variability. Recent years have witnessed dramatic improvements in the diagnostics, classification, and treatment of MM. However, patients with high-risk disease have not yet benefited from therapeutic advances. High-risk patients are often primary refractory to treatment or relapse early, ultimately resulting in progression toward aggressive end-stage MM, with associated extramedullary disease or plasma cell leukemia. Therefore, novel treatment modalities are needed to improve the outcomes of these patients. Bispecific antibodies (BsAbs) are immunotherapeutics that simultaneously target and thereby redirect effector immune cells to tumor cells. BsAbs have shown high efficacy in B cell malignancies, including refractory/relapsed acute lymphoblastic leukemia. Various BsAbs targeting MM-specific antigens such as B cell maturation antigen (BCMA), CD38, and CD138 are currently in pre-clinical and clinical development, with promising results. In this review, we outline these advances, focusing on BsAb drugs, their targets, and their potential to improve survival, especially for high-risk MM patients. In combination with current treatment strategies, BsAbs may pave the way toward a cure for MM.
Collapse
|
|
38
|
Figueiredo CR, Kalirai H, Sacco JJ, Azevedo RA, Duckworth A, Slupsky JR, Coulson JM, Coupland SE. Loss of BAP1 expression is associated with an immunosuppressive microenvironment in uveal melanoma, with implications for immunotherapy development. J Pathol 2020; 250:420-439. [PMID: 31960425 PMCID: PMC7216965 DOI: 10.1002/path.5384] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 12/28/2019] [Accepted: 01/14/2020] [Indexed: 12/22/2022]
Abstract
Immunotherapy using immune checkpoint inhibitors (ICIs) induces durable responses in many metastatic cancers. Metastatic uveal melanoma (mUM), typically occurring in the liver, is one of the most refractory tumours to ICIs and has dismal outcomes. Monosomy 3 (M3), polysomy 8q, and BAP1 loss in primary uveal melanoma (pUM) are associated with poor prognoses. The presence of tumour-infiltrating lymphocytes (TILs) within pUM and surrounding mUM - and some evidence of clinical responses to adoptive TIL transfer - strongly suggests that UMs are indeed immunogenic despite their low mutational burden. The mechanisms that suppress TILs in pUM and mUM are unknown. We show that BAP1 loss is correlated with upregulation of several genes associated with suppressive immune responses, some of which build an immune suppressive axis, including HLA-DR, CD38, and CD74. Further, single-cell analysis of pUM by mass cytometry confirmed the expression of these and other markers revealing important functions of infiltrating immune cells in UM, most being regulatory CD8+ T lymphocytes and tumour-associated macrophages (TAMs). Transcriptomic analysis of hepatic mUM revealed similar immune profiles to pUM with BAP1 loss, including the expression of IDO1. At the protein level, we observed TAMs and TILs entrapped within peritumoural fibrotic areas surrounding mUM, with increased expression of IDO1, PD-L1, and β-catenin (CTNNB1), suggesting tumour-driven immune exclusion and hence the immunotherapy resistance. These findings aid the understanding of how the immune response is organised in BAP1 - mUM, which will further enable functional validation of detected biomarkers and the development of focused immunotherapeutic approaches. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Collapse
Affiliation(s)
- Carlos R Figueiredo
- Department of Molecular and Clinical Cancer Medicine, ITMUniversity of LiverpoolLiverpoolUK
- Department of the Faculty of Medicine, MediCity Research Laboratory and Institute of BiomedicineUniversity of TurkuTurkuFinland
| | - Helen Kalirai
- Department of Molecular and Clinical Cancer Medicine, ITMUniversity of LiverpoolLiverpoolUK
| | - Joseph J Sacco
- Department of Molecular and Clinical Cancer Medicine, ITMUniversity of LiverpoolLiverpoolUK
- Department of Medical OncologyThe Clatterbridge Cancer CentreWirralUK
| | - Ricardo A Azevedo
- Department of Cancer BiologyThe University of Texas–MD Anderson Cancer CenterHoustonTXUSA
| | - Andrew Duckworth
- Department of Molecular and Clinical Cancer Medicine, ITMUniversity of LiverpoolLiverpoolUK
| | - Joseph R Slupsky
- Department of Molecular and Clinical Cancer Medicine, ITMUniversity of LiverpoolLiverpoolUK
| | - Judy M Coulson
- Department of Cellular and Molecular PhysiologyUniversity of LiverpoolLiverpoolUK
| | - Sarah E Coupland
- Department of Molecular and Clinical Cancer Medicine, ITMUniversity of LiverpoolLiverpoolUK
- Liverpool Clinical LaboratoriesRoyal Liverpool University HospitalLiverpoolUK
| |
Collapse
|
|
39
|
Hajaj E, Eisenberg G, Klein S, Frankenburg S, Merims S, Ben David I, Eisenhaure T, Henrickson SE, Villani AC, Hacohen N, Abudi N, Abramovich R, Cohen JE, Peretz T, Veillette A, Lotem M. SLAMF6 deficiency augments tumor killing and skews toward an effector phenotype revealing it as a novel T cell checkpoint. eLife 2020; 9:e52539. [PMID: 32122464 PMCID: PMC7075692 DOI: 10.7554/elife.52539] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 02/11/2020] [Indexed: 12/29/2022] Open
Abstract
SLAMF6 is a homotypic receptor of the Ig-superfamily whose exact role in immune modulation has remained elusive. Its constitutive expression on resting and activated T cells precludes it from being a bona fide exhaustion marker. By breeding Pmel-1 mice with SLAMF6 -/- mice, we generated donors for T cells lacking SLAMF6 and expressing a transgenic TCR for gp100-melanoma antigen. Activated Pmel-1xSLAMF6 -/- CD8+ T cells displayed improved polyfunctionality and strong tumor cytolysis. T-bet was the dominant transcription factor in Pmel-1 x SLAMF6 -/- cells, and upon activation, they acquired an effector-memory phenotype. Adoptive transfer of Pmel-1 x SLAMF6 -/- T cells to melanoma-bearing mice resulted in lasting tumor regression in contrast to temporary responses achieved with Pmel-1 T cells. LAG-3 expression was elevated in the SLAMF6 -/- cells, and the addition of the LAG-3-blocking antibody to the adoptive transfer protocol improved the SLAMF6 -/- T cells and expedited the antitumor response even further. The results from this study support the notion that SLAMF6 is an inhibitory immune receptor whose absence enables powerful CD8+ T cells to eradicate tumors.
Collapse
Affiliation(s)
- Emma Hajaj
- Sharett Institute of Oncology, Hadassah Hebrew University HospitalJerusalemIsrael
- Wohl Institute for Translational Medicine, Hadassah Medical OrganizationJerusalemIsrael
- Lautenberg Center for Immunology and Cancer Research, Faculty of Medicine, Hebrew UniversityJerusalemIsrael
| | - Galit Eisenberg
- Sharett Institute of Oncology, Hadassah Hebrew University HospitalJerusalemIsrael
- Wohl Institute for Translational Medicine, Hadassah Medical OrganizationJerusalemIsrael
| | - Shiri Klein
- Sharett Institute of Oncology, Hadassah Hebrew University HospitalJerusalemIsrael
- Wohl Institute for Translational Medicine, Hadassah Medical OrganizationJerusalemIsrael
| | - Shoshana Frankenburg
- Sharett Institute of Oncology, Hadassah Hebrew University HospitalJerusalemIsrael
- Wohl Institute for Translational Medicine, Hadassah Medical OrganizationJerusalemIsrael
| | - Sharon Merims
- Sharett Institute of Oncology, Hadassah Hebrew University HospitalJerusalemIsrael
- Wohl Institute for Translational Medicine, Hadassah Medical OrganizationJerusalemIsrael
| | - Inna Ben David
- Sharett Institute of Oncology, Hadassah Hebrew University HospitalJerusalemIsrael
- Wohl Institute for Translational Medicine, Hadassah Medical OrganizationJerusalemIsrael
| | | | - Sarah E Henrickson
- Broad Institute of MIT and HarvardCambridgeUnited States
- Boston Children's Hospital, Department of PediatricsBostonUnited States
| | - Alexandra Chloé Villani
- Broad Institute of MIT and HarvardCambridgeUnited States
- Center for Cancer Research, Massachusetts General HospitalCharlestownUnited States
- Department of Medicine, Harvard Medical SchoolBostonUnited States
- Center for Immunology and Inflammatory Diseases, Massachusetts General HospitalCharlestownUnited States
| | - Nir Hacohen
- Broad Institute of MIT and HarvardCambridgeUnited States
- Center for Cancer Research, Massachusetts General HospitalCharlestownUnited States
- Department of Medicine, Harvard Medical SchoolBostonUnited States
| | - Nathalie Abudi
- Wohl Institute for Translational Medicine, Hadassah Medical OrganizationJerusalemIsrael
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University HospitalJerusalemIsrael
| | - Rinat Abramovich
- Wohl Institute for Translational Medicine, Hadassah Medical OrganizationJerusalemIsrael
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University HospitalJerusalemIsrael
| | - Jonathan E Cohen
- Sharett Institute of Oncology, Hadassah Hebrew University HospitalJerusalemIsrael
- Wohl Institute for Translational Medicine, Hadassah Medical OrganizationJerusalemIsrael
| | - Tamar Peretz
- Sharett Institute of Oncology, Hadassah Hebrew University HospitalJerusalemIsrael
| | | | - Michal Lotem
- Sharett Institute of Oncology, Hadassah Hebrew University HospitalJerusalemIsrael
- Wohl Institute for Translational Medicine, Hadassah Medical OrganizationJerusalemIsrael
- Lautenberg Center for Immunology and Cancer Research, Faculty of Medicine, Hebrew UniversityJerusalemIsrael
| |
Collapse
|
|
40
|
O’Connell P, Amalfitano A, Aldhamen YA. SLAM Family Receptor Signaling in Viral Infections: HIV and Beyond. Vaccines (Basel) 2019; 7:E184. [PMID: 31744090 PMCID: PMC6963180 DOI: 10.3390/vaccines7040184] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 11/04/2019] [Accepted: 11/13/2019] [Indexed: 02/06/2023] Open
Abstract
The signaling lymphocytic activation molecule (SLAM) family of receptors are expressed on the majority of immune cells. These receptors often serve as self-ligands, and play important roles in cellular communication and adhesion, thus modulating immune responses. SLAM family receptor signaling is differentially regulated in various immune cell types, with responses generally being determined by the presence or absence of two SLAM family adaptor proteins-Ewing's sarcoma-associated transcript 2 (EAT-2) and SLAM-associated adaptor protein (SAP). In addition to serving as direct regulators of the immune system, certain SLAM family members have also been identified as direct targets for specific microbes and viruses. Here, we will discuss the known roles for these receptors in the setting of viral infection, with special emphasis placed on HIV infection. Because HIV causes such complex dysregulation of the immune system, studies of the roles for SLAM family receptors in this context are particularly exciting.
Collapse
Affiliation(s)
- Patrick O’Connell
- Department of Microbiology and Molecular Genetics, College of Osteopathic Medicine, Michigan State University, East Lansing, MI 48824, USA, (A.A.)
| | - Andrea Amalfitano
- Department of Microbiology and Molecular Genetics, College of Osteopathic Medicine, Michigan State University, East Lansing, MI 48824, USA, (A.A.)
- Department of Pediatrics, College of Osteopathic Medicine, Michigan State University, East Lansing, MI 48824, USA
| | - Yasser A. Aldhamen
- Department of Microbiology and Molecular Genetics, College of Osteopathic Medicine, Michigan State University, East Lansing, MI 48824, USA, (A.A.)
| |
Collapse
|
|
41
|
Gerth E, Mattner J. The Role of Adaptor Proteins in the Biology of Natural Killer T (NKT) Cells. Front Immunol 2019; 10:1449. [PMID: 31293596 PMCID: PMC6603179 DOI: 10.3389/fimmu.2019.01449] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 06/10/2019] [Indexed: 12/31/2022] Open
Abstract
Adaptor proteins contribute to the selection, differentiation and activation of natural killer T (NKT) cells, an innate(-like) lymphocyte population endowed with powerful immunomodulatory properties. Distinct from conventional T lymphocytes NKT cells preferentially home to the liver, undergo a thymic maturation and differentiation process and recognize glycolipid antigens presented by the MHC class I-like molecule CD1d on antigen presenting cells. NKT cells express a semi-invariant T cell receptor (TCR), which combines the Vα14-Jα18 chain with a Vβ2, Vβ7, or Vβ8 chain in mice and the Vα24 chain with the Vβ11 chain in humans. The avidity of interactions between their TCR, the presented glycolipid antigen and CD1d govern the selection and differentiation of NKT cells. Compared to TCR ligation on conventional T cells engagement of the NKT cell TCR delivers substantially stronger signals, which trigger the unique NKT cell developmental program. Furthermore, NKT cells express a panoply of primarily inhibitory NK cell receptors (NKRs) that control their self-reactivity and avoid autoimmune activation. Adaptor proteins influence NKT cell biology through the integration of TCR, NKR and/or SLAM (signaling lymphocyte-activation molecule) receptor signals or the variation of CD1d-restricted antigen presentation. TCR and NKR ligation engage the SH2 domain-containing leukocyte protein of 76kDa slp-76 whereas the SLAM associated protein SAP serves as adaptor for the SLAM receptor family. Indeed, the selection and differentiation of NKT cells selectively requires co-stimulation via SLAM receptors. Furthermore, SAP deficiency causes X-linked lymphoproliferative disease with multiple immune defects including a lack of circulating NKT cells. While a deletion of slp-76 leads to a complete loss of all peripheral T cell populations, mutations in the SH2 domain of slp-76 selectively affect NKT cell biology. Furthermore, adaptor proteins influence the expression and trafficking of CD1d in antigen presenting cells and subsequently selection and activation of NKT cells. Adaptor protein complex 3 (AP-3), for example, is required for the efficient presentation of glycolipid antigens which require internalization and processing. Thus, our review will focus on the complex contribution of adaptor proteins to the delivery of TCR, NKR and SLAM receptor signals in the unique biology of NKT cells and CD1d-restricted antigen presentation.
Collapse
MESH Headings
- Adaptor Protein Complex 3/immunology
- Adaptor Protein Complex 3/metabolism
- Adaptor Proteins, Signal Transducing/immunology
- Adaptor Proteins, Signal Transducing/metabolism
- Animals
- Antigen Presentation/immunology
- Antigens, CD1d/immunology
- Antigens, CD1d/metabolism
- Humans
- Lymphocyte Activation/immunology
- Mice
- Natural Killer T-Cells/immunology
- Natural Killer T-Cells/metabolism
- Phosphoproteins/immunology
- Phosphoproteins/metabolism
- Receptors, Antigen, T-Cell/immunology
- Receptors, Antigen, T-Cell/metabolism
- Receptors, Natural Killer Cell/immunology
- Receptors, Natural Killer Cell/metabolism
- Signaling Lymphocytic Activation Molecule Family/immunology
- Signaling Lymphocytic Activation Molecule Family/metabolism
Collapse
Affiliation(s)
| | - Jochen Mattner
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| |
Collapse
|
|
42
|
Xu Y, Liu Q, Zhong M, Wang Z, Chen Z, Zhang Y, Xing H, Tian Z, Tang K, Liao X, Rao Q, Wang M, Wang J. 2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies. J Hematol Oncol 2019; 12:49. [PMID: 31097020 PMCID: PMC6524286 DOI: 10.1186/s13045-019-0732-7] [Citation(s) in RCA: 131] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 04/10/2019] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Chimeric antigen receptor engineered T cells (CAR-T) have demonstrated extraordinary efficacy in B cell malignancy therapy and have been approved by the US Food and Drug Administration for diffuse large B cell lymphoma and acute B lymphocytic leukemia treatment. However, treatment of T cell malignancies using CAR-T cells remains limited due to the shared antigens between malignant T cells and normal T cells. CD5 is considered one of the important characteristic markers of malignant T cells and is expressed on almost all normal T cells but not on NK-92 cells. Recently, NK-92 cells have been utilized as CAR-modified immune cells. However, in preclinical models, CAR-T cells seem to be superior to CAR-NK-92 cells. Therefore, we speculate that in addition to the short lifespan of NK-92 cells in mice, the costimulatory domain used in CAR constructs might not be suitable for CAR-NK-92 cell engineering. METHODS Two second-generation anti-CD5 CAR plasmids with different costimulatory domains were constructed, one using the T-cell-associated activating receptor-4-1BB (BB.z) and the other using a NK-cell-associated activating receptor-2B4 (2B4.z). Subsequently, BB.z-NK and 2B4.z-NK were generated. Specific cytotoxicity against CD5+ malignant cell lines, primary CD5+ malignant cells, and normal T cells was evaluated in vitro. Moreover, a CD5+ T cell acute lymphoblastic leukemia (T-ALL) mouse model was established and used to assess the efficacy of CD5-CAR NK immunotherapy in vivo. RESULTS Both BB.z-NK and 2B4.z-NK exhibited specific cytotoxicity against CD5+ malignant cells in vitro and prolonged the survival of T-ALL xenograft mice. Encouragingly, 2B4.z-NK cells displayed greater anti-CD5+ malignancy capacity than that of BB.z-NK, accompanied by a greater direct lytic side effect versus BB.z-NK. CONCLUSIONS Anti-CD5 CAR-NK cells, particularly those constructed with the intracellular domain of NK-cell-associated activating receptor 2B4, may be a promising strategy for T cell malignancy treatment.
Collapse
Affiliation(s)
- Yingxi Xu
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Qian Liu
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Mengjun Zhong
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Zhenzhen Wang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Zhaoqi Chen
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Yu Zhang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Haiyan Xing
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Zheng Tian
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Kejing Tang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Xiaolong Liao
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Qing Rao
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Min Wang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China.
| | - Jianxiang Wang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China. .,National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China.
| |
Collapse
|
|
43
|
Xu Y, Liu Q, Zhong M, Wang Z, Chen Z, Zhang Y, Xing H, Tian Z, Tang K, Liao X, Rao Q, Wang M, Wang J. 2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies. J Hematol Oncol 2019. [PMID: 31097020 DOI: 10.1186/s13045-019-0732-7/figures/5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/20/2023] Open
Abstract
BACKGROUND Chimeric antigen receptor engineered T cells (CAR-T) have demonstrated extraordinary efficacy in B cell malignancy therapy and have been approved by the US Food and Drug Administration for diffuse large B cell lymphoma and acute B lymphocytic leukemia treatment. However, treatment of T cell malignancies using CAR-T cells remains limited due to the shared antigens between malignant T cells and normal T cells. CD5 is considered one of the important characteristic markers of malignant T cells and is expressed on almost all normal T cells but not on NK-92 cells. Recently, NK-92 cells have been utilized as CAR-modified immune cells. However, in preclinical models, CAR-T cells seem to be superior to CAR-NK-92 cells. Therefore, we speculate that in addition to the short lifespan of NK-92 cells in mice, the costimulatory domain used in CAR constructs might not be suitable for CAR-NK-92 cell engineering. METHODS Two second-generation anti-CD5 CAR plasmids with different costimulatory domains were constructed, one using the T-cell-associated activating receptor-4-1BB (BB.z) and the other using a NK-cell-associated activating receptor-2B4 (2B4.z). Subsequently, BB.z-NK and 2B4.z-NK were generated. Specific cytotoxicity against CD5+ malignant cell lines, primary CD5+ malignant cells, and normal T cells was evaluated in vitro. Moreover, a CD5+ T cell acute lymphoblastic leukemia (T-ALL) mouse model was established and used to assess the efficacy of CD5-CAR NK immunotherapy in vivo. RESULTS Both BB.z-NK and 2B4.z-NK exhibited specific cytotoxicity against CD5+ malignant cells in vitro and prolonged the survival of T-ALL xenograft mice. Encouragingly, 2B4.z-NK cells displayed greater anti-CD5+ malignancy capacity than that of BB.z-NK, accompanied by a greater direct lytic side effect versus BB.z-NK. CONCLUSIONS Anti-CD5 CAR-NK cells, particularly those constructed with the intracellular domain of NK-cell-associated activating receptor 2B4, may be a promising strategy for T cell malignancy treatment.
Collapse
Affiliation(s)
- Yingxi Xu
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Qian Liu
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Mengjun Zhong
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Zhenzhen Wang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Zhaoqi Chen
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Yu Zhang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Haiyan Xing
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Zheng Tian
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Kejing Tang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Xiaolong Liao
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Qing Rao
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Min Wang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China.
| | - Jianxiang Wang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China.
- National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China.
| |
Collapse
|
|
44
|
Cruz-Muñoz ME, Valenzuela-Vázquez L, Sánchez-Herrera J, Santa-Olalla Tapia J. From the "missing self" hypothesis to adaptive NK cells: Insights of NK cell-mediated effector functions in immune surveillance. J Leukoc Biol 2019; 105:955-971. [PMID: 30848847 DOI: 10.1002/jlb.mr0618-224rr] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 01/29/2019] [Accepted: 02/04/2019] [Indexed: 12/11/2022] Open
Abstract
The original discovery of NK cells approximately 40 yr ago was based on their unique capability to kill tumor cells without prior sensitization or priming, a process named natural cytotoxicity. Since then, several studies have documented that NK cells can kill hematopoietic and nonhematopoietic cancer cells. NK cells also recognize and kill cells that have undergone viral infections. Besides natural cytotoxicity, NK cells are also major effectors of antibody-dependent cell cytotoxicity (ADCC). Therefore, NK cells are well "armed" to recognize and mount immune responses against "insults" that result from cell transformation and viral infections. Because of these attributes, an essential role of NK cells in tumor surveillance was noted. Indeed, several studies have shown a correlation between impaired NK cell cytotoxicity and a higher risk of developing cancer. This evidence led to the idea that cancer initiation and progress is intimately related to an abnormal or misdirected immune response. Whereas all these ideas remain current, it is also true that NK cells represent a heterogeneous population with different abilities to secrete cytokines and to mediate cytotoxic functions. In addition, recent data has shown that NK cells are prone to suffer epigenetic modifications resulting in the acquisition of previously unrecognized attributes such as memory and long-term survival. Such NK cells, referred as "adaptive" or "memory-like," also display effector functions that are not necessarily equal to those observed in conventional NK cells. Given the new evidence available, it is essential to discuss the conceptual reasoning and misconceptions regarding the role of NK cells in immune surveillance and immunotherapy.
Collapse
|
|
45
|
Lu Y, Zhong MC, Qian J, Calderon V, Cruz Tleugabulova M, Mallevaey T, Veillette A. SLAM receptors foster iNKT cell development by reducing TCR signal strength after positive selection. Nat Immunol 2019; 20:447-457. [DOI: 10.1038/s41590-019-0334-0] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 01/25/2019] [Indexed: 12/23/2022]
|
|
46
|
Kumar S, Leigh ND, Cao X. The Role of Co-stimulatory/Co-inhibitory Signals in Graft-vs.-Host Disease. Front Immunol 2018; 9:3003. [PMID: 30627129 PMCID: PMC6309815 DOI: 10.3389/fimmu.2018.03003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 12/05/2018] [Indexed: 12/31/2022] Open
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective immunotherapeutic approach for various hematologic and immunologic ailments. Despite the beneficial impact of allo-HCT, its adverse effects cause severe health concerns. After transplantation, recognition of host cells as foreign entities by donor T cells induces graft-vs.-host disease (GVHD). Activation, proliferation and trafficking of donor T cells to target organs and tissues are critical steps in the pathogenesis of GVHD. T cell activation is a synergistic process of T cell receptor (TCR) recognition of major histocompatibility complex (MHC)-anchored antigen and co-stimulatory/co-inhibitory signaling in the presence of cytokines. Most of the currently used therapeutic regimens for GVHD are based on inhibiting the allogeneic T cell response or T-cell depletion (TCD). However, the immunosuppressive drugs and TCD hamper the therapeutic potential of allo-HCT, resulting in attenuated graft-vs.-leukemia (GVL) effect as well as increased vulnerability to infection. In view of the drawback of overbroad immunosuppression, co-stimulatory, and co-inhibitory molecules are plausible targets for selective modulation of T cell activation and function that can improve the effectiveness of allo-HCT. Therefore, this review collates existing knowledge of T cell co-stimulation and co-inhibition with current research that may have the potential to provide novel approaches to cure GVHD without sacrificing the beneficial effects of allo-HCT.
Collapse
Affiliation(s)
- Sandeep Kumar
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Nicholas D Leigh
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Xuefang Cao
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States.,Department of Microbiology and Immunology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, United States
| |
Collapse
|
|
47
|
Kumar P, Bhattacharya P, Prabhakar BS. A comprehensive review on the role of co-signaling receptors and Treg homeostasis in autoimmunity and tumor immunity. J Autoimmun 2018; 95:77-99. [PMID: 30174217 PMCID: PMC6289740 DOI: 10.1016/j.jaut.2018.08.007] [Citation(s) in RCA: 144] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 08/22/2018] [Accepted: 08/26/2018] [Indexed: 12/22/2022]
Abstract
The immune system ensures optimum T-effector (Teff) immune responses against invading microbes and tumor antigens while preventing inappropriate autoimmune responses against self-antigens with the help of T-regulatory (Treg) cells. Thus, Treg and Teff cells help maintain immune homeostasis through mutual regulation. While Tregs can contribute to tumor immune evasion by suppressing anti-tumor Teff response, loss of Treg function can result in Teff responses against self-antigens leading to autoimmune disease. Thus, loss of homeostatic balance between Teff/Treg cells is often associated with both cancer and autoimmunity. Co-stimulatory and co-inhibitory receptors, collectively known as co-signaling receptors, play an indispensable role in the regulation of Teff and Treg cell expansion and function and thus play critical roles in modulating autoimmune and anti-tumor immune responses. Over the past three decades, considerable efforts have been made to understand the biology of co-signaling receptors and their role in immune homeostasis. Mutations in co-inhibitory receptors such as CTLA4 and PD1 are associated with Treg dysfunction, and autoimmune diseases in mice and humans. On the other hand, growing tumors evade immune surveillance by exploiting co-inhibitory signaling through expression of CTLA4, PD1 and PDL-1. Immune checkpoint blockade (ICB) using anti-CTLA4 and anti-PD1 has drawn considerable attention towards co-signaling receptors in tumor immunology and created renewed interest in studying other co-signaling receptors, which until recently have not been as well studied. In addition to co-inhibitory receptors, co-stimulatory receptors like OX40, GITR and 4-1BB have also been widely implicated in immune homeostasis and T-cell stimulation, and use of agonistic antibodies against OX40, GITR and 4-1BB has been effective in causing tumor regression. Although ICB has seen unprecedented success in cancer treatment, autoimmune adverse events arising from ICB due to loss of Treg homeostasis poses a major obstacle. Herein, we comprehensively review the role of various co-stimulatory and co-inhibitory receptors in Treg biology and immune homeostasis, autoimmunity, and anti-tumor immunity. Furthermore, we discuss the autoimmune adverse events arising upon targeting these co-signaling receptors to augment anti-tumor immune responses.
Collapse
Affiliation(s)
- Prabhakaran Kumar
- Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA
| | - Palash Bhattacharya
- Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA
| | - Bellur S Prabhakar
- Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA; Department of Ophthalmology, Associate Dean for Technological Innovation and Training, University of Illinois College of Medicine, Room E-705, (M/C 790), 835 S. Wolcott Ave, Chicago, IL, 60612, USA.
| |
Collapse
|
|
48
|
Yigit B, Wang N, Herzog RW, Terhorst C. SLAMF6 in health and disease: Implications for therapeutic targeting. Clin Immunol 2018; 204:3-13. [PMID: 30366106 DOI: 10.1016/j.clim.2018.10.013] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Revised: 10/22/2018] [Accepted: 10/22/2018] [Indexed: 12/20/2022]
Affiliation(s)
- Burcu Yigit
- Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
| | - Ninghai Wang
- Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Roland W Herzog
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Cox Terhorst
- Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
| |
Collapse
|
|
49
|
Dragovich MA, Mor A. The SLAM family receptors: Potential therapeutic targets for inflammatory and autoimmune diseases. Autoimmun Rev 2018; 17:674-682. [PMID: 29729453 DOI: 10.1016/j.autrev.2018.01.018] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 01/18/2018] [Indexed: 12/20/2022]
Abstract
The signaling lymphocytic activation molecule (SLAM) family is comprised of nine distinct receptors (SLAMF1 through SLAMF9) that are expressed on hematopoietic cells. All of these receptors, with the exception of SLAMF4, are homotypic by nature as downstream signaling occurs when hematopoietic cells that express the same SLAM receptor interact. The SLAM family receptor function is largely controlled via SLAM associated protein (SAP) family adaptors. The SAP family adaptors consist of SAP, Ewing sarcoma associated transcript (EAT)-2, and EAT-2-related transducer (ERT). These adaptors associate with the cytoplasmic domain of the SLAM family receptors through phosphorylated tyrosines. Defects in SLAM family members and SAP adaptors have been implicated in causing immune deficiencies. This is exemplified in patients with X-linked lymphoproliferative (XLP) disease, where SAP undergoes a loss of function mutation. Furthermore, evidence has been accumulating that SLAM family members are potential targets for inflammatory and autoimmune diseases. This review will discuss the structure and function of the SLAM family receptors and SAP family adaptors, their role in immune regulation, and potential approaches to target this family of receptors therapeutically.
Collapse
Affiliation(s)
- Matthew A Dragovich
- Department of Medicine, Division of Rheumatology, NYU School of Medicine, New York, NY 10016, USA; Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA
| | - Adam Mor
- Department of Medicine, Division of Rheumatology, NYU School of Medicine, New York, NY 10016, USA; Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA.
| |
Collapse
|
|
50
|
Abstract
Natural killer (NK) cells express an array of germ-line encoded receptors that are capable of triggering cytotoxicity. NK cells tend to express many members of a given family of signalling molecules. The presence of many activating receptors and many members of a given family of signalling molecules can enable NK cells to detect different kinds of target cells, and to mount different kinds of responses. This contributes also to the robustness of NK cells responses; cytotoxic functions of NK cells often remain unaffected in the absence of selected signalling molecules. NK cells express many MHC-I-specific inhibitory receptors. Signals from MHC-I-specific inhibitory receptors tightly control NK cell cytotoxicity and, paradoxically, maintain NK cells in a state of proper responsiveness. This review provides a brief overview of the events that underlie NK cell activation, and how signals from inhibitory receptors intercept NK cell activation to prevent inappropriate triggering of cytotoxicity.
Collapse
Affiliation(s)
- Santosh Kumar
- CSIR-Centre for Cellular and Molecular Biology, Hyderabad, Telangana, India
| |
Collapse
|