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Hsieh LL, Thompson EA, Jairam NP, Roznik K, Figueroa A, Aytenfisu T, Zhou W, Gour N, Chao KH, Milstone AM, Egbert E, D'Alessio F, Karakousis PC, Ordoñez A, Scully EP, Pekosz A, Karaba AH, Cox AL. SARS-CoV-2 induces neutrophil degranulation and differentiation into myeloid-derived suppressor cells associated with severe COVID-19. Sci Transl Med 2025; 17:eadn7527. [PMID: 40397714 DOI: 10.1126/scitranslmed.adn7527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 11/18/2024] [Accepted: 04/01/2025] [Indexed: 05/23/2025]
Abstract
Severe COVID-19 presents with a distinct immunological profile, characterized by elevated neutrophil and reduced lymphocyte counts, seen commonly in fungal and bacterial infections. This study demonstrates that patients hospitalized with COVID-19 show evidence of neutrophil degranulation and have increased expression of neutrophil surface lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a marker of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Both early LOX-1 and programmed death-ligand 1 (PD-L1) expression on neutrophils were associated with development of severe disease. To determine whether tissue damage or inflammation is required to induce PMN-MDSCs or whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly activates neutrophils to become PMN-MDSCs, we incubated healthy human neutrophils with SARS-CoV-2. SARS-CoV-2 rapidly induced LOX-1 surface expression in healthy neutrophils independent of productive infection. LOX-1 induction was dependent on granule exocytosis and promoted up-regulation of reactive oxygen species, CD63, and PD-L1, enabling LOX-1+ neutrophils to suppress autologous T cell proliferation in vitro. These results support a role for PMN-MDSCs in mediating severe COVID-19, and inhibition of PD-L1 represents a potential therapeutic strategy for enhancing the immune response in acute SARS-CoV-2 infection.
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Affiliation(s)
- Leon L Hsieh
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA
| | - Elizabeth A Thompson
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA
| | - Nirvani P Jairam
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Katerina Roznik
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA
| | - Alexis Figueroa
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Tihitina Aytenfisu
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Weiqiang Zhou
- Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA
| | - Naina Gour
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Kuan-Hao Chao
- Center for Computational Biology, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Aaron M Milstone
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Emily Egbert
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Franco D'Alessio
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Petros C Karakousis
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA
- Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21287, USA
| | - Alvaro Ordoñez
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Eileen P Scully
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Andrew Pekosz
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA
| | - Andrew H Karaba
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Andrea L Cox
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
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Kim EY, Abides J, Keller CR, Martinez SR, Li W. Tumor Microenvironment Lactate: Is It a Cancer Progression Marker, Immunosuppressant, and Therapeutic Target? Molecules 2025; 30:1763. [PMID: 40333742 PMCID: PMC12029365 DOI: 10.3390/molecules30081763] [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: 03/10/2025] [Revised: 04/12/2025] [Accepted: 04/12/2025] [Indexed: 05/09/2025] Open
Abstract
The "Warburg effect" is a term coined a century ago for the preferential use of glycolysis over aerobic respiration in tumor cells for energy production, even under aerobic conditions. Although this is a less efficient mechanism of generating energy from glucose, aerobic glycolysis, in addition to the canonical anaerobic glycolysis, is an effective means of lactate production. The abundant waste product, lactate, yielded by the dual glycolysis in a tumor, has been discovered to be a major biomolecule that drives cancer progression. Lactate is a metabolic energy source that, via cell membrane lactate transporters, shuttles in and out of cancer cells as well as cancer cell-associated stromal cells and immune cells within the tumor microenvironment (TME). Additionally, lactate serves as a pH tuner, signaling ligand and transducer, epigenetic and gene transcription regulator, TME modifier, immune suppressor, chemoresistance modulator, and prognostic marker. With such broad functionalities, the production-consumption-reproduction of TME lactate fuels tumor growth and dissemination. Here, we elaborate on the lactate sources that contribute to the pool of lactate in the TME, the functions of TME lactate, the influence of the TME lactate on immune cell function and local tissue immunity, and anticancer therapeutic approaches adopting lactate manipulations and their efficacies. By scrutinizing these properties of the TME lactate and others that have been well addressed in the field, it is expected that a better weighing of the influence of the TME lactate on cancer development, progression, prognosis, and therapeutic efficacy can be achieved.
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Affiliation(s)
- Eugene Y. Kim
- Department of Translational Medicine and Physiology, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA 99202, USA; (E.Y.K.); (J.A.); (C.R.K.)
| | - Joyce Abides
- Department of Translational Medicine and Physiology, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA 99202, USA; (E.Y.K.); (J.A.); (C.R.K.)
- Doctor of Medicine Program, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA 99202, USA
| | - Chandler R. Keller
- Department of Translational Medicine and Physiology, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA 99202, USA; (E.Y.K.); (J.A.); (C.R.K.)
| | - Steve R. Martinez
- Department of Medical Education and Clinical Sciences, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA 99202, USA
- Providence Regional Cancer Partnership, Providence Regional Medical Center, Everett, WA 98201, USA
| | - Weimin Li
- Department of Translational Medicine and Physiology, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA 99202, USA; (E.Y.K.); (J.A.); (C.R.K.)
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Taheri M, Tehrani HA, Farzad SA, Korourian A, Arefian E, Ramezani M. The potential of mesenchymal stem cell coexpressing cytosine deaminase and secretory IL18-FC chimeric cytokine in suppressing glioblastoma recurrence. Int Immunopharmacol 2024; 142:113048. [PMID: 39236459 DOI: 10.1016/j.intimp.2024.113048] [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: 05/09/2024] [Revised: 08/28/2024] [Accepted: 08/28/2024] [Indexed: 09/07/2024]
Abstract
Glioblastoma multiforme (GBM) patients have a high recurrence rate of 90%, and the 5-year survival rate is only about 5%. Cytosine deaminase (CDA)/5-fluorocytosine (5-FC) gene therapy is a promising glioma treatment as 5-FC can cross the blood-brain barrier (BBB), while 5-fluorouracil (5-FU) cannot. Furthermore, 5-FU can assist reversing the immunological status of cold solid tumors. This study developed mesenchymal stem cells (MSCs) co-expressing yeast CDA and the secretory IL18-FC superkine to prevent recurrent tumor progression by simultaneously exerting cytotoxic effects and enhancing immune responses. IL18 was fused with Igk and IgG2a FC domains to enhance its secretion and serum half-life. The study confirmed the expression and activity of the CDA enzyme, as well as the expression, secretion, and activity of secretory IL18 and IL18-FC superkine, which were expressed by lentiviruses transduced-MSCs. In the transwell tumor-tropism assay, it was observed that the genetically modified MSCs retained their selective tumor-tropism ability following transduction. CDA-expressing MSCs, in the presence of 5-FC (200 µg/ml), induced cell cycle arrest and apoptosis in glioma cells through bystander effects in an indirect transwell co-culture system. They reduced the viability of the direct co-culture system when they constituted only 12.5 % of the cell population. The effectiveness of engineered MSCs in suppressing tumor progression was assessed by intracerebral administration of a lethal dose of GL261 cells combined in a ratio of 1:1 with MSCs expressing CDA, or CDA and sIL18, or CDA and sIL18-FC, into C57BL/6 mice. PET scan showed no conspicuous tumor mass in the MSC-CDA-sIL18-FC group that received 5-FC treatment. The pathological analysis showed that tumor progression suppressed in this group until 20th day after cell inoculation. Cytokine assessment showed that both interferon-gamma (IFN-γ) and interleukin-4 (IL-4) increased in the serum of MSC-CDA-sIL18 and MSC-CDA-sIL18-FC, treated with normal saline (NS) compared to those of the control group. The MSC-CDA-sIL18-FC group that received 5-FC treatment showed reduced serum levels of IL-6 and a considerably improved survival rate compared to the control group. Therefore, MSCs co-expressing yeast CDA and secretory IL18-FC, with tumor tropism capability, may serve as a supplementary approach to standard GBM treatment to effectively inhibit tumor progression and prevent recurrence.
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Affiliation(s)
- Mojtaba Taheri
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hossein Abdul Tehrani
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Sara Amel Farzad
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Korourian
- Quality Control Department Pathobiology Laboratory Center, Tehran, Iran
| | - Ehsan Arefian
- Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran; Stem Cells Technology and Tissue Regeneration Department, School of Biology, College of Science, University of Tehran, Tehran, Iran.
| | - Mohammad Ramezani
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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Li M, Zhao X. Leukocyte immunoglobulin-like receptor B4 (LILRB4) in acute myeloid leukemia: From prognostic biomarker to immunotherapeutic target. Chin Med J (Engl) 2024; 137:2697-2711. [PMID: 38973293 PMCID: PMC11611246 DOI: 10.1097/cm9.0000000000003195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Indexed: 07/09/2024] Open
Abstract
ABSTRACT Leukocyte immunoglobulin-like receptor (LILR) B4 (also known as ILT3/CD85k) is an immune checkpoint protein that is highly expressed in solid tumors and hematological malignancies and plays a significant role in the pathophysiology of cancer. LILRB4 is highly expressed in acute myeloid leukemia (AML), and this phenotype is associated with adverse patient outcomes. Its differential expression in tumors compared to normal tissues, its presence in tumor stem cells, and its multifaceted roles in tumorigenesis position it as a promising therapeutic target in AML. Currently, several immunotherapies targeting LILRB4 are undergoing clinical trials. This review summarizes advancements made in the study of LILRB4 in AML, focusing on its structure, ligands, expression, and significance in normal tissues and AML; its protumorigenic effects and mechanisms in AML; and the application of LILRB4-targeted therapies in AML. These insights highlight the potential advantages of LILRB4 as an immunotherapeutic target in the context of AML.
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Affiliation(s)
- Muzi Li
- Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, National Clinical Research Center for Hematologic Disease, Beijing 100044, China
| | - Xiangyu Zhao
- Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, National Clinical Research Center for Hematologic Disease, Beijing 100044, China
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Britton WR, Cioffi I, Stonebraker C, Spence M, Okolo O, Martin C, Henick B, Nakagawa H, Parikh AS. Advancements in TGF-β Targeting Therapies for Head and Neck Squamous Cell Carcinoma. Cancers (Basel) 2024; 16:3047. [PMID: 39272905 PMCID: PMC11394608 DOI: 10.3390/cancers16173047] [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: 07/25/2024] [Revised: 08/24/2024] [Accepted: 08/28/2024] [Indexed: 09/15/2024] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cause of cancer worldwide according to GLOBOCAN estimates from 2022. Current therapy options for recurrent or metastatic disease are limited to conventional cytotoxic chemotherapy and immunotherapy, with few targeted therapy options readily available. Recent single-cell transcriptomic analyses identified TGF-β signaling as an important mediator of functional interplays between cancer-associated fibroblasts and a subset of mesenchymal cancer cells. This signaling was shown to drive invasiveness, treatment resistance, and immune evasion. These data provide renewed interest in the TGF-β pathway as an alternative therapeutic target, prompting a critical review of previous clinical data which suggest a lack of benefit from TGF-β inhibitors. While preclinical data have demonstrated the great anti-tumorigenic potential of TGF-β inhibitors, the underwhelming results of ongoing and completed clinical trials highlight the difficulty actualizing these benefits into clinical practice. This topical review will discuss the relevant preclinical and clinical findings for TGF-β inhibitors in HNSCC and will explore the potential role of patient stratification in the development of this therapeutic strategy.
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Affiliation(s)
- William R Britton
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
- Columbia Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Isabel Cioffi
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
| | - Corinne Stonebraker
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
| | - Matthew Spence
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
- Columbia Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Ogoegbunam Okolo
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
- Columbia Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Cecilia Martin
- Organoid and Cell Culture Core, Columbia University Digestive and Liver Diseases Research Center, Columbia University, New York, NY 10032, USA
| | - Brian Henick
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
| | - Hiroshi Nakagawa
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
- Organoid and Cell Culture Core, Columbia University Digestive and Liver Diseases Research Center, Columbia University, New York, NY 10032, USA
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY 10032, USA
| | - Anuraag S Parikh
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
- Department of Otolaryngology-Head and Neck Surgery, Columbia University, New York, NY 10032, USA
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6
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Li MS, Wang XH, Wang H. Immunomodulation of Proton-activated G Protein-coupled Receptors in Inflammation. Curr Med Sci 2024; 44:475-484. [PMID: 38748372 DOI: 10.1007/s11596-024-2872-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 03/22/2024] [Indexed: 06/29/2024]
Abstract
Proton-activated G protein-coupled receptors (GPCRs), initially discovered by Ludwig in 2003, are widely distributed in various tissues. These receptors have been found to modulate the immune system in several inflammatory diseases, including inflammatory bowel disease, atopic dermatitis, and asthma. Proton-activated GPCRs belong to the G protein-coupled receptor family and can detect alternations in extracellular pH. This detection triggers downstream signaling pathways within the cells, ultimately influencing the function of immune cells. In this review, we specifically focused on investigating the immune response of proton-activated GPCRs under inflammatory conditions.
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Affiliation(s)
- Min-Shan Li
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Institute of Allergy and Clinical Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Clinical Research Center for Nasal Inflammatory Diseases, Wuhan, 430030, China
| | - Xiang-Hong Wang
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Institute of Allergy and Clinical Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Clinical Research Center for Nasal Inflammatory Diseases, Wuhan, 430030, China
| | - Heng Wang
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Institute of Allergy and Clinical Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Hubei Clinical Research Center for Nasal Inflammatory Diseases, Wuhan, 430030, China.
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Volk-Draper L, Athaiya S, Espinosa Gonzalez M, Bhattarai N, Wilber A, Ran S. Tumor microenvironment restricts IL-10 induced multipotent progenitors to myeloid-lymphatic phenotype. PLoS One 2024; 19:e0298465. [PMID: 38640116 PMCID: PMC11029653 DOI: 10.1371/journal.pone.0298465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 01/24/2024] [Indexed: 04/21/2024] Open
Abstract
Lymphangiogenesis is induced by local pro-lymphatic growth factors and bone marrow (BM)-derived myeloid-lymphatic endothelial cell progenitors (M-LECP). We previously showed that M-LECP play a significant role in lymphangiogenesis and lymph node metastasis in clinical breast cancer (BC) and experimental BC models. We also showed that differentiation of mouse and human M-LECP can be induced through sequential activation of colony stimulating factor-1 (CSF-1) and Toll-like receptor-4 (TLR4) pathways. This treatment activates the autocrine interleukin-10 (IL-10) pathway that, in turn, induces myeloid immunosuppressive M2 phenotype along with lymphatic-specific proteins. Because IL-10 is implicated in differentiation of numerous lineages, we sought to determine whether this pathway specifically promotes the lymphatic phenotype or multipotent progenitors that can give rise to M-LECP among other lineages. Analyses of BM cells activated either by CSF-1/TLR4 ligands in vitro or orthotopic breast tumors in vivo showed expansion of stem/progenitor population and coincident upregulation of markers for at least four lineages including M2-macrophage, lymphatic endothelial, erythroid, and T-cells. Induction of cell plasticity and multipotency was IL-10 dependent as indicated by significant reduction of stem cell markers and those for multiple lineages in differentiated cells treated with anti-IL-10 receptor (IL-10R) antibody or derived from IL-10R knockout mice. However, multipotent CD11b+/Lyve-1+/Ter-119+/CD3e+ progenitors detected in BM appeared to split into a predominant myeloid-lymphatic fraction and minor subsets expressing erythroid and T-cell markers upon establishing tumor residence. Each sub-population was detected at a distinct intratumoral site. This study provides direct evidence for differences in maturation status between the BM progenitors and those reaching tumor destination. The study results suggest preferential tumor bias towards expansion of myeloid-lymphatic cells while underscoring the role of IL-10 in early BM production of multipotent progenitors that give rise to both hematopoietic and endothelial lineages.
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Affiliation(s)
- Lisa Volk-Draper
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, United States of America
| | - Shaswati Athaiya
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, United States of America
| | - Maria Espinosa Gonzalez
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, United States of America
| | - Nihit Bhattarai
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, United States of America
| | - Andrew Wilber
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, United States of America
- Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL, United States of America
| | - Sophia Ran
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, United States of America
- Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL, United States of America
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Shin HS, Kim S, Jin SM, Yoo YJ, Heo JH, Lim YT. Molecular Masking of Synthetic Immunomodulator Evokes Antitumor Immunity With Reduced Immune Tolerance and Systemic Toxicity by Temporal Activity Recovery and Sustained Stimulation. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2309039. [PMID: 37903320 DOI: 10.1002/adma.202309039] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 10/17/2023] [Indexed: 11/01/2023]
Abstract
Activation of the innate immune system counteracts tumor-induced immunosuppression. Hence, small molecule-based toll-like receptor 7/8 agonists (TLR7/8a), which can modulate immunosuppression in the tumor microenvironment along with the activation of innate immunity, are emerging as essential components of cancer immunotherapy. However, the clinical application of synthetic TLR7/8a therapies is limited by systemic immune-associated toxicity and immune tolerance induced by uncontrolled stimulatory activities and repeated treatments. To address these limitations, a dynamic immunomodulation strategy incorporating masking and temporal recovery of the activity of TLR7/8a through prodrug-like TLR7/8a (pro-TLR7/8a) at the molecular level and a sustained and controlled release of active TLR7/8a from nanoliposome (pro-TLR7/8a) (NL(pro-TLR7/8)) in a macroscale depot are designed. Immunization with cationic NL(pro-TLR7/8) and anionic antigens triggers robust activation of innate immune cells as well as antigen-specific T cell responses, eliciting reprogramming of immunosuppressive cells into tumor-suppressive cells, with decreased systemic adverse effects and immune tolerance. Combination treatment with NL(pro-TLR7/8a) and immune checkpoint inhibitors (anti-CTLA-4 plus anti-PD-L1) or nanoliposomes (Doxorubicin) has synergistic effects on antitumor immunity in various tumor models. The concept of pro-TLR7/8a suggested herein may facilitate the advancement of small-molecule-based immunomodulators for clinical translation and safe and effective cancer immunotherapy.
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Affiliation(s)
- Hong Sik Shin
- SKKU Advanced Institute of Nanotechnology (SAINT), Department of Nano Science and Technology, Department of Nano Engineering, School of Chemical Engineering, Sungkyunkwan University (SKKU), 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do, 16419, Republic of Korea
| | - Sohyun Kim
- SKKU Advanced Institute of Nanotechnology (SAINT), Department of Nano Science and Technology, Department of Nano Engineering, School of Chemical Engineering, Sungkyunkwan University (SKKU), 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do, 16419, Republic of Korea
| | - Seung Mo Jin
- SKKU Advanced Institute of Nanotechnology (SAINT), Department of Nano Science and Technology, Department of Nano Engineering, School of Chemical Engineering, Sungkyunkwan University (SKKU), 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do, 16419, Republic of Korea
| | - Yeon Jeong Yoo
- SKKU Advanced Institute of Nanotechnology (SAINT), Department of Nano Science and Technology, Department of Nano Engineering, School of Chemical Engineering, Sungkyunkwan University (SKKU), 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do, 16419, Republic of Korea
| | - Jang Hun Heo
- SKKU Advanced Institute of Nanotechnology (SAINT), Department of Nano Science and Technology, Department of Nano Engineering, School of Chemical Engineering, Sungkyunkwan University (SKKU), 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do, 16419, Republic of Korea
| | - Yong Taik Lim
- SKKU Advanced Institute of Nanotechnology (SAINT), Department of Nano Science and Technology, Department of Nano Engineering, School of Chemical Engineering, Sungkyunkwan University (SKKU), 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do, 16419, Republic of Korea
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Ruzanova VS, Kirikovich SS, Levites EV, Proskurina AS, Dolgova EV, Ritter GS, Efremov YR, Dubatolova TD, Sysoev AV, Koleno DI, Ostanin AA, Chernykh ER, Bogachev SS. The Macrophage Activator GcMAF-RF Enhances the Antitumor Effect of Karanahan Technology through Induction of M2-M1 Macrophage Reprogramming. J Immunol Res 2024; 2024:7484490. [PMID: 38455363 PMCID: PMC10919980 DOI: 10.1155/2024/7484490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 10/03/2023] [Accepted: 02/19/2024] [Indexed: 03/09/2024] Open
Abstract
Macrophages are the immune cells of high-immunological plasticity, which can exert both pro- and anti-inflammatory activity, as well as repolarize their phenotype to the opposite or neutral one. In this regard, M2 macrophages of the tumor-associated stroma (TAS) are a promising therapeutic target in treating malignant neoplasms. Using FACS assay, we have estimated the CD11b+/Ly-6G+/Ly-6C+ fraction of macrophages from the peritoneum and TAS in intact healthy mice and those with developed Lewis carcinoma, both untreated and treated according to Karanahan technology in combination with group-specific macrophage activator (GcMAF-RF). As well, the pattern of pro- and anti-inflammatory cytokines mRNA expression in different groups of experimental and tumor-bearing animals was assessed. It was found that: (i) exposure of intact mice to GcMAF-RF results in the increased number of CD11b+/Ly-6C+ peritoneal macrophages and, at the same time, the expression pattern of cytokines in peritoneal macrophages switches from that characteristic of the mixed M1/M2 phenotype to that characteristic of the neutral M0 one; (ii) combination of Karanahan technology and GcMAF-RF treatment results in M0/M1 repolarization of TAS macrophages; (iii) in tumor-bearing mice, the response of peritoneal macrophages to such a treatment is associated with the induction of anti-inflammatory reaction, which is opposite to that in TAS macrophages.
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Affiliation(s)
- Vera S. Ruzanova
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - Svetlana S. Kirikovich
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - Evgeniy V. Levites
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - Anastasia S. Proskurina
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - Evgeniya V. Dolgova
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - Genrikh S. Ritter
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - Yaroslav R. Efremov
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
- Novosibirsk National Research State University, Novosibirsk, Russia
| | - Tatyana D. Dubatolova
- Institute of Molecular and Cellular Biology, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - Alexander V. Sysoev
- N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - Danil I. Koleno
- N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - Alexandr A. Ostanin
- Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
| | - Elena R. Chernykh
- Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
| | - Sergey S. Bogachev
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
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10
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Che K, Luo Y, Song X, Yang Z, Wang H, Shi T, Wang Y, Wang X, Wu H, Yu L, Liu B, Wei J. Macrophages reprogramming improves immunotherapy of IL-33 in peritoneal metastasis of gastric cancer. EMBO Mol Med 2024; 16:251-266. [PMID: 38238529 PMCID: PMC10897402 DOI: 10.1038/s44321-023-00012-y] [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: 12/18/2022] [Revised: 09/24/2023] [Accepted: 11/20/2023] [Indexed: 02/17/2024] Open
Abstract
Peritoneal metastasis (PM) has a suppressive tumor immune microenvironment (TIME) that limits the effects of immunotherapy. This study aimed to investigate the immunomodulatory effects of intraperitoneal administration of IL-33, a cytokine that is reported to potentiate antitumor immunity and inhibit metastasis. We found survival was significantly prolonged in patients with high IL-33 mRNA expression. In immunocompetent mice, intraperitoneal administration of IL-33 could induce a celiac inflammatory environment, activate immunologic effector cells, and reverse the immunosuppressive tumor microenvironment, which effectively delayed tumor progression and PM of gastric cancer. Mechanistically, IL-33 could induce M2 polarization by activating p38-GATA-binding protein 3 signaling. IL-33 combined with anti-CSF1R or p38 inhibitor to regulate tumor-associated macrophages (TAMs) had a synergistic antitumor effect. Inducing a local inflammatory milieu by IL-33 administration provided a novel approach for treating peritoneal metastasis, which, when combined with TAM reprogramming to reshape TIME, can achieve better treatment efficacy.
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Affiliation(s)
- Keying Che
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
- Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yuting Luo
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Xueru Song
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Zhe Yang
- Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Hanbing Wang
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Tao Shi
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Yue Wang
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Xuan Wang
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Department of Pathology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Hongyan Wu
- Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Lixia Yu
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Baorui Liu
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Jia Wei
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
- Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, China.
- Engineering Research Center of Protein and Peptide Medicine, Ministry of Education, Nanjing, China.
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11
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Qi YQ, Xiong F, Chen YJ. The correlation between tumor-associated macrophages and the prognosis of east Asian hepatocellular carcinoma patients: A systematic review and meta-analysis. Pathol Res Pract 2023; 252:154919. [PMID: 37939428 DOI: 10.1016/j.prp.2023.154919] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 10/29/2023] [Accepted: 11/01/2023] [Indexed: 11/10/2023]
Abstract
BACKGROUND Previous related studies have found that the levels of tumor-associated macrophages (TAMs) were correlated with prognoses in hepatocellular carcinoma. However, the prognostic value of TAMs for East Asian HCC patients remains inconclusive. METHODS Our objectives were to systematically review the performance and explore the prognostic and clinical value of TAMs in patients with HCC. A total of 23 relevant studies of 4389 patients were included into our meta-analysis. And the work has been reported in line with PRISMA guidelines. RESULTS The results demonstrated that increased expression level of peritumoral infiltrated CD68+ macrophages had a poor prognostic value on overall survival (OS), disease free survival (DFS) and recurrence-free survival (RFS). However, there was no correlation between disease-free survival (DFS) and the abundance of CD68+ TAMs both in intratumoral regions. Additionally, low density of CD169+, high density of CD206, and high density of CD204+ TAMs had a worse prognostic value on OS while the CD163+ TAMs had no diagnostic value on OS. The densities of CD68+ TAMs exhibited significantly correlation with AFP level and vascular invasion. The levels of CD169+ TAMs showed apparent relation to vascular invasion and TNM stages. CONCLUSION These findings indicate that TAMs may accomplish as significant prognostic biomarkers for East Asian HCC patients. However, further researches should be performed to estimate the clinical value of TAMs in HCC.
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Affiliation(s)
- Yong-Qiang Qi
- Department of Biliary-pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Fei Xiong
- Department of Biliary-pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Yong-Jun Chen
- Department of Biliary-pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
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12
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Chaudhri A, Bu X, Wang Y, Gomez M, Torchia JA, Hua P, Hung SH, Davies MA, Lizee GA, von Andrian U, Hwu P, Freeman GJ. The CX3CL1-CX3CR1 chemokine axis can contribute to tumor immune evasion and blockade with a novel CX3CR1 monoclonal antibody enhances response to anti-PD-1 immunotherapy. Front Immunol 2023; 14:1237715. [PMID: 37771579 PMCID: PMC10524267 DOI: 10.3389/fimmu.2023.1237715] [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: 06/09/2023] [Accepted: 08/28/2023] [Indexed: 09/30/2023] Open
Abstract
CX3CL1 secreted in the tumor microenvironment serves as a chemoattractant playing a critical role in metastasis of CX3CR1 expressing cancer cells. CX3CR1 can be expressed in both cancer and immune-inhibitory myeloid cells to facilitate their migration. We generated a novel monoclonal antibody against mouse CX3CR1 that binds to CX3CR1 and blocks the CX3CL1-CX3CR1 interaction. We next explored the immune evasion strategies implemented by the CX3CL1-CX3CR1 axis and find that it initiates a resistance program in cancer cells that results in 1) facilitation of tumor cell migration, 2) secretion of soluble mediators to generate a pro-metastatic niche, 3) secretion of soluble mediators to attract myeloid populations, and 4) generation of tumor-inflammasome. The CX3CR1 monoclonal antibody reduces migration of tumor cells and decreases secretion of immune suppressive soluble mediators by tumor cells. In combination with anti-PD-1 immunotherapy, this CX3CR1 monoclonal antibody enhances survival in an immunocompetent mouse colon carcinoma model through a decrease in tumor-promoting myeloid populations. Thus, this axis is involved in the mechanisms of resistance to anti-PD-1 immunotherapy and the combination therapy can overcome a portion of the resistance mechanisms to anti-PD-1.
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Affiliation(s)
- Apoorvi Chaudhri
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
- Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, United States
- Department of Medicine, Harvard Medical School, Boston, MA, United States
| | - Xia Bu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
- Department of Medicine, Harvard Medical School, Boston, MA, United States
| | - Yunfei Wang
- Department of Clinical Science, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Michael Gomez
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
- Department of Medicine, Harvard Medical School, Boston, MA, United States
| | - James A. Torchia
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
- Department of Medicine, Harvard Medical School, Boston, MA, United States
| | - Ping Hua
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
- Department of Medicine, Harvard Medical School, Boston, MA, United States
| | - Shao-Hsi Hung
- Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, United States
| | - Michael A. Davies
- Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Gregory A. Lizee
- Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Ulrich von Andrian
- Department of Medicine, Harvard Medical School, Boston, MA, United States
- Department of Immunology & HMS Center for Immune Imaging, Harvard Medical School, Boston, MA, United States
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, United States
| | - Patrick Hwu
- Department of Clinical Science, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Gordon J. Freeman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
- Department of Medicine, Harvard Medical School, Boston, MA, United States
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13
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Yuan J. CCR2: A characteristic chemokine receptor in normal and pathological intestine. Cytokine 2023; 169:156292. [PMID: 37437448 DOI: 10.1016/j.cyto.2023.156292] [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: 05/10/2023] [Revised: 06/25/2023] [Accepted: 07/01/2023] [Indexed: 07/14/2023]
Abstract
C-C motif chemokine receptor 2 (CCR2), together with its ligands, especially C-C motif ligand 2 (CCL2), to which CCR2 has the highest affinity, form a noteworthy signaling pathway in recruiting macrophages for the immune responses among variegated disorders in vivo environment. Scientometric methods are used to analyze intestine-related CCR2 expression. We describe the current knowledge on biological function of CCR2 in physiological intestine in three dimensions, namely its effects on stromal cells, angiogenesis, and remodeling. However, anomalous expression of CCR2 has also been conveyed to correlate with detrimental outcomes in intestine, such as infective colitis, inflammatory bowel disease, carcinogenesis, and colon-related metastasis. In this article, we briefly summarize recent experimental works on CCR2 and its ligands, mostly CCL2, in intestinal-related physiological and pathological states to ravel out their working mechanisms in intestinal diseases.
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Affiliation(s)
- Jin Yuan
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China.
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14
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Ren J, Xu B, Ren J, Liu Z, Cai L, Zhang X, Wang W, Li S, Jin L, Ding L. The Importance of M1-and M2-Polarized Macrophages in Glioma and as Potential Treatment Targets. Brain Sci 2023; 13:1269. [PMID: 37759870 PMCID: PMC10526262 DOI: 10.3390/brainsci13091269] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 08/25/2023] [Accepted: 08/30/2023] [Indexed: 09/29/2023] Open
Abstract
Glioma is the most common and malignant tumor of the central nervous system. Glioblastoma (GBM) is the most aggressive glioma, with a poor prognosis and no effective treatment because of its high invasiveness, metabolic rate, and heterogeneity. The tumor microenvironment (TME) contains many tumor-associated macrophages (TAMs), which play a critical role in tumor proliferation, invasion, metastasis, and angiogenesis and indirectly promote an immunosuppressive microenvironment. TAM is divided into tumor-suppressive M1-like (classic activation of macrophages) and tumor-supportive M2-like (alternatively activated macrophages) polarized cells. TAMs exhibit an M1-like phenotype in the initial stages of tumor progression, and along with the promotion of lysing tumors and the functions of T cells and NK cells, tumor growth is suppressed, and they rapidly transform into M2-like polarized macrophages, which promote tumor progression. In this review, we discuss the mechanism by which M1- and M2-polarized macrophages promote or inhibit the growth of glioblastoma and indicate the future directions for treatment.
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Affiliation(s)
- Jiangbin Ren
- Department of neurosurgery, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Nanjing Medical University, Huai’an 223000, China; (J.R.); (B.X.); (Z.L.); (L.C.); (X.Z.); (W.W.); (S.L.); (L.J.)
| | - Bangjie Xu
- Department of neurosurgery, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Nanjing Medical University, Huai’an 223000, China; (J.R.); (B.X.); (Z.L.); (L.C.); (X.Z.); (W.W.); (S.L.); (L.J.)
| | - Jianghao Ren
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200030, China;
| | - Zhichao Liu
- Department of neurosurgery, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Nanjing Medical University, Huai’an 223000, China; (J.R.); (B.X.); (Z.L.); (L.C.); (X.Z.); (W.W.); (S.L.); (L.J.)
| | - Lingyu Cai
- Department of neurosurgery, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Nanjing Medical University, Huai’an 223000, China; (J.R.); (B.X.); (Z.L.); (L.C.); (X.Z.); (W.W.); (S.L.); (L.J.)
| | - Xiaotian Zhang
- Department of neurosurgery, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Nanjing Medical University, Huai’an 223000, China; (J.R.); (B.X.); (Z.L.); (L.C.); (X.Z.); (W.W.); (S.L.); (L.J.)
| | - Weijie Wang
- Department of neurosurgery, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Nanjing Medical University, Huai’an 223000, China; (J.R.); (B.X.); (Z.L.); (L.C.); (X.Z.); (W.W.); (S.L.); (L.J.)
| | - Shaoxun Li
- Department of neurosurgery, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Nanjing Medical University, Huai’an 223000, China; (J.R.); (B.X.); (Z.L.); (L.C.); (X.Z.); (W.W.); (S.L.); (L.J.)
| | - Luhao Jin
- Department of neurosurgery, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Nanjing Medical University, Huai’an 223000, China; (J.R.); (B.X.); (Z.L.); (L.C.); (X.Z.); (W.W.); (S.L.); (L.J.)
| | - Lianshu Ding
- Department of neurosurgery, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Nanjing Medical University, Huai’an 223000, China; (J.R.); (B.X.); (Z.L.); (L.C.); (X.Z.); (W.W.); (S.L.); (L.J.)
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15
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Li S, Wang C, Chen J, Lan Y, Zhang W, Kang Z, Zheng Y, Zhang R, Yu J, Li W. Signaling pathways in brain tumors and therapeutic interventions. Signal Transduct Target Ther 2023; 8:8. [PMID: 36596785 PMCID: PMC9810702 DOI: 10.1038/s41392-022-01260-z] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 11/16/2022] [Accepted: 11/21/2022] [Indexed: 01/05/2023] Open
Abstract
Brain tumors, although rare, contribute to distinct mortality and morbidity at all ages. Although there are few therapeutic options for brain tumors, enhanced biological understanding and unexampled innovations in targeted therapies and immunotherapies have considerably improved patients' prognoses. Nonetheless, the reduced response rates and unavoidable drug resistance of currently available treatment approaches have become a barrier to further improvement in brain tumor (glioma, meningioma, CNS germ cell tumors, and CNS lymphoma) treatment. Previous literature data revealed that several different signaling pathways are dysregulated in brain tumor. Importantly, a better understanding of targeting signaling pathways that influences malignant behavior of brain tumor cells might open the way for the development of novel targeted therapies. Thus, there is an urgent need for a more comprehensive understanding of the pathogenesis of these brain tumors, which might result in greater progress in therapeutic approaches. This paper began with a brief description of the epidemiology, incidence, risk factors, as well as survival of brain tumors. Next, the major signaling pathways underlying these brain tumors' pathogenesis and current progress in therapies, including clinical trials, targeted therapies, immunotherapies, and system therapies, have been systemically reviewed and discussed. Finally, future perspective and challenges of development of novel therapeutic strategies in brain tumor were emphasized.
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Affiliation(s)
- Shenglan Li
- grid.24696.3f0000 0004 0369 153XDepartment of Neuro-Oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Can Wang
- grid.24696.3f0000 0004 0369 153XDepartment of Neuro-Oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Jinyi Chen
- grid.24696.3f0000 0004 0369 153XDepartment of Neuro-Oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Yanjie Lan
- grid.24696.3f0000 0004 0369 153XDepartment of Neuro-Oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Weichunbai Zhang
- grid.24696.3f0000 0004 0369 153XDepartment of Neuro-Oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Zhuang Kang
- grid.24696.3f0000 0004 0369 153XDepartment of Neuro-Oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Yi Zheng
- grid.24696.3f0000 0004 0369 153XDepartment of Neuro-Oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Rong Zhang
- grid.24696.3f0000 0004 0369 153XDepartment of Neuro-Oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Jianyu Yu
- grid.24696.3f0000 0004 0369 153XDepartment of Neuro-Oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Wenbin Li
- Department of Neuro-Oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
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16
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Abdollahi E, Johnston TP, Ghaneifar Z, Vahedi P, Goleij P, Azhdari S, Moghaddam AS. Immunomodulatory Therapeutic Effects of Curcumin on M1/M2 Macrophage Polarization in Inflammatory Diseases. Curr Mol Pharmacol 2023; 16:2-14. [PMID: 35331128 DOI: 10.2174/1874467215666220324114624] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 07/02/2021] [Accepted: 08/16/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Due to their plasticity, macrophages exert critical effects on both promoting and suppressing inflammatory processes. Pathologic inflammatory conditions are frequently correlated with dynamic alterations in macrophage activation, with classically activated M1 cells associated with the promotion and maintenance of inflammation and M2 cells being linked to the resolution or smouldering of chronic inflammation. Inflammation deputes a common feature of various chronic diseases and the direct involvement in the insurgence and development of these conditions. Macrophages participate in an autoregulatory loop characterizing the inflammatory process, as they produce a wide range of biologically active mediators that exert either deleterious or beneficial effects during the inflammation. Therefore, balancing the favorable ratios of M1/M2 macrophages can help ameliorate the inflammatory landscape of pathologic conditions. Curcumin is a component of turmeric with many pharmacological properties. OBJECTIVE Recent results from both in-vivo and in-vitro studies have indicated that curcumin can affect polarization and/or functions of macrophage subsets in the context of inflammation-related diseases. There is no comprehensive review of the impact of curcumin on cytokines involved in macrophage polarization in the context of inflammatory diseases. The present review will cover some efforts to explore the underlying molecular mechanisms by which curcumin modulates the macrophage polarization in distant pathological inflammatory conditions, such as cancer, autoimmunity, renal inflammation, stroke, atherosclerosis, and macrophage-driven pathogenesis. RESULTS The accumulation of the findings from in vitro and in vivo experimental studies suggests that curcumin beneficially influences M1 and M2 macrophages in a variety of inflammatory diseases with unfavorable macrophage activation. CONCLUSION Curcumin not only enhances anti-tumor immunity (via shifting M polarization towards M1 phenotype and/or up-regulation of M1 markers expression) but ameliorates inflammatory diseases, including autoimmune diseases (experimental autoimmune myocarditis and Behcet's disease), nephropathy, chronic serum sickness, stroke, and atherosclerosis.
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Affiliation(s)
- Elham Abdollahi
- Department of Gynecology, Woman Health Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Immunology and Allergy, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Thomas P Johnston
- Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Missouri, USA
| | - Zahra Ghaneifar
- Department of Nutrition, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Parviz Vahedi
- Department of Anatomical Sciences, Maragheh University of Medical Sciences, Maragheh, Iran
| | - Pouya Goleij
- Department of Genetics, Faculty of Biology, Sana Institute of Higher Education, Sari, Iran
| | - Sara Azhdari
- Department of Anatomy and Embryology, School of Medicine, Bam University of Medical Sciences, Bam, Iran
| | - Abbas Shapouri Moghaddam
- Department of Immunology, Bu-Ali Research Institute, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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17
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Tamma R, Ingravallo G, Annese T, d’Amati A, Lorusso L, Ribatti D. Tumor Microenvironment and Microvascular Density in Human Glioblastoma. Cells 2022; 12:cells12010011. [PMID: 36611806 PMCID: PMC9818990 DOI: 10.3390/cells12010011] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/09/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022] Open
Abstract
Glioblastoma (GBM) is a very aggressive form of cancer affecting the central nervous system. Although it occurs almost exclusively in the brain, glioblastoma can also appear in the brainstem, cerebellum, and spinal cord. It is characterized by high rates of proliferation, invasion, and necrosis. Moreover, GBM is a highly vascularized tumor and presents resistance to therapy. Recent data indicate that GBM cells are surrounded by a microenvironment (TME) which includes a complex network constituted of cellular/extracellular components and vessels able to influence both tumor growth and angiogenesis. In this retrospective study, we evaluated 30 bioptic specimens of adult patients diagnosed with IDH1 wild type GBM taken at the time of the first diagnosis. Each section has been divided into two experimental zones: the tumor side and the healthy surrounding tissue. We performed a series of immunohistochemical stainings with the purpose of evaluating the presence of total and M2 macrophages, CD4+-, CD8+-lymphocytes, and CD34+ microvessels. In addition, we have also evaluated the percentage of cells expressing bcl6 and p53 to determine any possible correlations with TME. Our data showed a significant increase in the total and M2 type macrophages, of CD4+ and CD8+ lymphocytes, and of CD34+ microvessels in the tumoral area respective to the healthy zone. We also confirmed our previous data showing the higher number of p53 and BCL6+ cells in the tumor area with a positive correlation between BCL6 and CD34+ microvessels. In conclusion, the data that came from this work support the important role played by microenvironment components in GBM progression. These results could contribute to the generation of new specific therapies useful in preventing GBM progression.
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Affiliation(s)
- Roberto Tamma
- Department of Translational Biomedicine and Neuroscience, University of Bari Medical School, 70124 Bari, Italy
- Correspondence: (R.T.); (D.R.); Tel.: +39-0805478323 (D.R.); Fax: +39-0805478310 (D.R.)
| | - Giuseppe Ingravallo
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Medical School, 70124 Bari, Italy
| | - Tiziana Annese
- Department of Translational Biomedicine and Neuroscience, University of Bari Medical School, 70124 Bari, Italy
- Department of Medicine and Surgery, Libera Università del Mediterraneo (LUM) Giuseppe Degennaro University, 70010 Bari, Italy
| | - Antonio d’Amati
- Department of Translational Biomedicine and Neuroscience, University of Bari Medical School, 70124 Bari, Italy
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Medical School, 70124 Bari, Italy
| | - Loredana Lorusso
- Department of Translational Biomedicine and Neuroscience, University of Bari Medical School, 70124 Bari, Italy
| | - Domenico Ribatti
- Department of Translational Biomedicine and Neuroscience, University of Bari Medical School, 70124 Bari, Italy
- Correspondence: (R.T.); (D.R.); Tel.: +39-0805478323 (D.R.); Fax: +39-0805478310 (D.R.)
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18
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Shigehiro T, Ueno M, Kijihira M, Takahashi R, Umemura C, Taha EA, Kurosaka C, Asayama M, Murakami H, Satoh A, Nakamura Y, Futami J, Masuda J. Immune State Conversion of the Mesenteric Lymph Node in a Mouse Breast Cancer Model. Int J Mol Sci 2022; 23:ijms231911035. [PMID: 36232335 PMCID: PMC9570492 DOI: 10.3390/ijms231911035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/17/2022] [Accepted: 09/18/2022] [Indexed: 11/16/2022] Open
Abstract
Secondary lymphoid tissues, such as the spleen and lymph nodes (LNs), contribute to breast cancer development and metastasis in both anti- and pro-tumoral directions. Although secondary lymphoid tissues have been extensively studied, very little is known about the immune conversion in mesenteric LNs (mLNs) during breast cancer development. Here, we demonstrate inflammatory immune conversion of mLNs in a metastatic 4T1 breast cancer model. Splenic T cells were significantly decreased and continuously suppressed IFN-γ production during tumor development, while myeloid-derived suppressor cells (MDSCs) were dramatically enriched. However, T cell numbers in the mLN did not decrease, and the MDSCs only moderately increased. T cells in the mLN exhibited conversion from a pro-inflammatory state with high IFN-γ expression to an anti-inflammatory state with high expression of IL-4 and IL-10 in early- to late-stages of breast cancer development. Interestingly, increased migration of CD103+CD11b+ dendritic cells (DCs) into the mLN, along with increased (1→3)-β-D-glucan levels in serum, was observed even in late-stage breast cancer. This suggests that CD103+CD11b+ DCs could prime cancer-reactive T cells. Together, the data indicate that the mLN is an important lymphoid tissue contributing to breast cancer development.
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Affiliation(s)
- Tsukasa Shigehiro
- Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Correspondence: (T.S.); (J.M.); Tel.: +81-47-121-4060 (T.S.); +81-86-251-8003 (J.M.)
| | - Maho Ueno
- Department of Applied Chemistry and Biotechnology, Faculty of Engineering, Okayama University, Okayama 700-8530, Japan
| | - Mayumi Kijihira
- Department of Applied Chemistry and Biotechnology, Faculty of Engineering, Okayama University, Okayama 700-8530, Japan
| | - Ryotaro Takahashi
- Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan
| | - Chiho Umemura
- Division of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan
| | - Eman A. Taha
- Division of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan
| | - Chisaki Kurosaka
- Department of Applied Chemistry and Biotechnology, Faculty of Engineering, Okayama University, Okayama 700-8530, Japan
| | - Megumi Asayama
- Department of Applied Chemistry and Biotechnology, Faculty of Engineering, Okayama University, Okayama 700-8530, Japan
| | - Hiroshi Murakami
- Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan
- Division of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan
| | - Ayano Satoh
- Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan
- Division of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan
| | - Yoshimasa Nakamura
- Graduate School of Environmental and Life Science, Okayama University, Okayama 700-8530, Japan
| | - Junichiro Futami
- Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan
- Division of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan
| | - Junko Masuda
- Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan
- Division of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan
- Department of Pharmacology, Tokyo Women’s Medical University, Shinjuku, Tokyo 162-8666, Japan
- Correspondence: (T.S.); (J.M.); Tel.: +81-47-121-4060 (T.S.); +81-86-251-8003 (J.M.)
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19
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Xin B, Yang M, Wu P, Du L, Deng X, Hui E, Feng GS. Enhancing the therapeutic efficacy of programmed death ligand 1 antibody for metastasized liver cancer by overcoming hepatic immunotolerance in mice. Hepatology 2022; 76:630-645. [PMID: 34860431 PMCID: PMC9163212 DOI: 10.1002/hep.32266] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 11/24/2021] [Accepted: 11/30/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Immunotherapy with programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) blockade has shown low response rates in liver cancer patients, with the underlying mechanisms unclear. To decipher a specific impact of the liver microenvironment, we compared the effects of anti-PD-L1 antibody (αPD-L1) blockade on the same tumor grown s.c. or in the liver. APPROACH AND RESULTS We generated s.c. tumors in mice by inoculating MC38 colorectal cancer (CRC) cells under the skin and metastatic liver tumors by portal vein or splenic injection of CRC cells. Tumor-bearing mice were treated by i.p. injection of αPD-L1, polyinosinic:polycytidylic acid (poly[I:C]), or both. αPD-L1 monotherapy significantly suppressed s.c. tumor growth, but showed no effect on metastatic liver tumors. However, the combination of αPD-L1 with poly(I:C), an innate immunity-stimulating reagent, robustly inhibited tumor progression in liver. The combination therapy effectively down-regulated myeloid-derived suppressor cells (MDSCs), but up-regulated ratios of M1/M2 macrophages, CD8/CD4, and CD8/regulatory T (Treg) cells infiltrated into liver tumors and whole liver. A group of long-lasting T-bet+ Eomes- PD-1- cytotoxic T cells was maintained in the combo-treated liver, leading to resistance to tumor recurrence. Depleting macrophages or blocking type Ⅰ interferon signaling abrogated the synergistic antitumor effect of αPD-L1 and poly(I:C), indicating a requirement of boosting innate immunity for optimized activation of cytotoxic T cells by PD-1/PD-L1 blockade. CONCLUSIONS The poor response of liver cancers to αPD-L1 therapy is largely attributable to a unique hepatic immunotolerant microenvironment, independent of tumor origins or types. The success of a combinatorial immunotherapy relies on coordinated inhibition or activation of various innate and adaptive immune cell activities.
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Affiliation(s)
- Bing Xin
- Department of Pathology, Division of Biological Sciences and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093
| | - Meixiang Yang
- Department of Pathology, Division of Biological Sciences and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093
| | - Panyisha Wu
- Department of Pathology, Division of Biological Sciences and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093
| | - Li Du
- Department of Pathology, Division of Biological Sciences and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093
| | - Xingyu Deng
- Department of Pathology, Division of Biological Sciences and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093
| | - Enfu Hui
- Section of Cell & Developmental Biology, Division of Biological Sciences, University of California at San Diego, La Jolla, CA 92093
| | - Gen-Sheng Feng
- Department of Pathology, Division of Biological Sciences and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093
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Translational landscape of glioblastoma immunotherapy for physicians: guiding clinical practice with basic scientific evidence. J Hematol Oncol 2022; 15:80. [PMID: 35690784 PMCID: PMC9188021 DOI: 10.1186/s13045-022-01298-0] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 05/10/2022] [Indexed: 02/06/2023] Open
Abstract
Despite recent advances in cancer therapeutics, glioblastoma (GBM) remains one of the most difficult cancers to treat in both the primary and recurrent settings. GBM presents a unique therapeutic challenge given the immune-privileged environment of the brain and the aggressive nature of the disease. Furthermore, it can change phenotypes throughout the course of disease—switching between mesenchymal, neural, and classic gene signatures, each with specific markers and mechanisms of resistance. Recent advancements in the field of immunotherapy—which utilizes strategies to reenergize or alter the immune system to target cancer—have shown striking results in patients with many types of malignancy. Immune checkpoint inhibitors, adoptive cellular therapy, cellular and peptide vaccines, and other technologies provide clinicians with a vast array of tools to design highly individualized treatment and potential for combination strategies. There are currently over 80 active clinical trials evaluating immunotherapies for GBM, often in combination with standard secondary treatment options including re-resection and anti-angiogenic agents, such as bevacizumab. This review will provide a clinically focused overview of the immune environment present in GBM, which is frequently immunosuppressive and characterized by M2 macrophages, T cell exhaustion, enhanced transforming growth factor-β signaling, and others. We will also outline existing immunotherapeutic strategies, with a special focus on immune checkpoint inhibitors, chimeric antigen receptor therapy, and dendritic cell vaccines. Finally, we will summarize key discoveries in the field and discuss currently active clinical trials, including combination strategies, burgeoning technology like nucleic acid and nanoparticle therapy, and novel anticancer vaccines. This review aims to provide the most updated summary of the field of immunotherapy for GBM and offer both historical perspective and future directions to help inform clinical practice.
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21
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IL-6 dependent expansion of inflammatory MDSCs (CD11b+ Gr-1+) promote Th-17 mediated immune response during experimental cerebral malaria. Cytokine 2022; 155:155910. [PMID: 35594680 DOI: 10.1016/j.cyto.2022.155910] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 05/03/2022] [Accepted: 05/05/2022] [Indexed: 12/18/2022]
Abstract
Myeloid derived suppressor cells (MDSCs) are a group of heterogeneous cell populations that can suppress T cell responses. Various aspects of MDSCs in regulating immune responses in several cancer and infectious diseases have been reported till date. But the role and regulation of MDSCs have not been systematically studied in the context of malaria. This study depicts the phenotypic and functional characteristics of splenic MDSCs and how they regulate Th-17 mediated immune response during Experimental Cerebral Malaria (ECM). Flow cytometric analysis reveals that MDSCs in the spleen and bone marrow expand at 8 dpi during ECM. Among subtypes of MDSCs, PMN-MDSCs show significant expansion in the spleen but M-MDSCs remain unaltered. Functional analysis of sorted MDSCs from spleens of Plasmodium berghei ANKA (PbA) infected mice shows suppressive nature of these cells and high production of Nitric oxide (NO). Besides, MDSCs were also found to express various inflammatory markers during ECM suggesting the M1 type phenotype of these cells. In-vivo depletion of MDSCs by the use of Anti Gr-1 increases mice survival but doesn't significantly alter the parasitemia. Previously, it has been reported that Treg/Th-17 balance in the spleen is skewed towards Th-17 during ECM. Depletion of MDSCs was found to regulate Th-17 percentages to homeostatic levels and subvert various inflammatory changes in the spleen. Among different factors, IL-6 was found to play an important role in the expansion of MDSCs and expression of inflammatory markers on MDSCs in a STAT3-dependent manner. These findings provide a unique insight into the role of IL-6 in the expansion of the MDSC population which causes inflammatory changes and increased Th-17 responses during ECM.
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22
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Su MT, Kumata S, Endo S, Okada Y, Takai T. LILRB4 promotes tumor metastasis by regulating MDSCs and inhibiting miR-1 family miRNAs. Oncoimmunology 2022; 11:2060907. [PMID: 35402083 PMCID: PMC8986222 DOI: 10.1080/2162402x.2022.2060907] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are a population of immune suppressive cells that are involved in tumor-associated immunosuppression, and dominate tumor progression and metastasis. In this study, we report that the leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4, murine ortholog gp49B) orchestrates the polarization of MDSCs to exhibit pro-tumor phenotypes. We found that gp49B deficiency inhibited tumor metastases of cancer cells, and reduced tumor-infiltration of monocytic MDSCs (M-MDSCs) in tumor-bearing mice. Gp49B−/− MDSCs inhibited pro-tumor immune responses, such as activation of Treg cells, promotion of cancer cell migration, and stimulation of tumor angiogenesis. Treatment of wild-type tumor-bearing mice with gp49B−/− M-MDSCs reduced cancer metastasis. Furthermore, gp49B knockout affected plasma exosome composition in terms of increased miR-1 family microRNAs (miRNAs) expression, which correlates with the upregulation of gp49B−/− MDSC-derived anti-tumor miRNAs. Collectively, our findings reveal that LILRB4/gp49B promotes MDSC-mediated tumor metastasis by regulating the M2-polarization of MDSCs and suppressing the secretion of miR-1 family miRNAs, which facilitate tumor migration and invasion. Abbreviations CTLA-4: cytotoxic T-lymphocyte-associated protein-4; FBS: fetal bovine serum; G-MDSCs: granulocytic-MDSCs; GP49B: glycoprotein 49B; HE: hematoxylin-eosin; ICI: immune checkpoint inhibitor; ITIM: immunoreceptor tyrosine-based inhibition motif; LILRB4: leukocyte immunoglobulin-like receptor B4; M-CSF: macrophage colony stimulating factor; MDSC: myeloid-derived suppressor cell; M-MDSC: monocytic MDSC; MMP-9: metallopeptidase-9; mAb: monoclonal antibody; PBS: phosphate-buffered saline; PCR: polymerase chain reaction; PD-1: programmed death-1; PD-L1: programmed death ligand-1; PMN-MDSC: polymorphonuclear-MDSC; qRT-PCR: quantitative reverse transcription PCR; TAM: tumor associated macrophage; TME: tumor microenvironment; TMM: trimmed mean of M value; VEGFA: vascular endothelial growth factor A
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Affiliation(s)
- Mei-Tzu Su
- Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Sakiko Kumata
- Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
- Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Shota Endo
- Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Yoshinori Okada
- Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Toshiyuki Takai
- Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
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23
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The Pivotal Immunoregulatory Functions of Microglia and Macrophages in Glioma Pathogenesis and Therapy. JOURNAL OF ONCOLOGY 2022; 2022:8903482. [PMID: 35419058 PMCID: PMC9001141 DOI: 10.1155/2022/8903482] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 03/24/2022] [Indexed: 12/16/2022]
Abstract
Gliomas are mixed solid tumors composed of both neoplastic and nonneoplastic cells. In glioma microenvironment, the most common nonneoplastic and infiltrating cells are macrophages and microglia. Microglia are the exact phagocytes of the central nervous system, whereas macrophages are myeloid immune cells that are depicted with ardent phagocytosis. Microglia are heterogeneously located in almost all nonoverlapping sections of the brain as well as the spinal cord, while macrophages are derived from circulating monocytes. Microglia and macrophages utilize a variety of receptors for the detection of molecules, particles, and cells that they engulf. Both microglia and peripheral macrophages interact directly with vessels both in the periphery of and within the tumor. In glioma milieu, normal human astrocytes, glioma cells, and microglia all exhibited the ability of phagocytosing glioma cells and precisely apoptotic tumor cells. Also, microglia and macrophages are robustly triggered by the glioma via the expression of chemoattractants such as monocyte chemoattractant protein, stromal-derived factor-1, and macrophage-colony stimulating factor. Glioma-associated microglia and/or macrophages positively correlated with glioma invasiveness, immunosuppression, and patients' poor outcome, making these cells a suitable target for immunotherapeutic schemes.
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24
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Yuan B, Wang G, Tang X, Tong A, Zhou L. Immunotherapy of glioblastoma: recent advances and future prospects. Hum Vaccin Immunother 2022; 18:2055417. [PMID: 35344682 PMCID: PMC9248956 DOI: 10.1080/21645515.2022.2055417] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Glioblastoma (GBM) stands out as the most common, aggressive form of primary malignant brain tumor conferring a devastatingly poor prognosis. Despite aggressive standard-of-care in surgical resection and chemoradiation with temozolomide, the median overall survival of patients still remains no longer than 15 months, due to significant tumor heterogeneity, immunosuppression induced by the tumor immune microenvironment and low mutational burden. Advances in immunotherapeutic approaches have revolutionized the treatment of various cancer types and become conceptually attractive for glioblastoma. In this review, we provide an overview of the basic knowledge underlying immune targeting and promising immunotherapeutic strategies including CAR T cells, oncolytic viruses, cancer vaccines, and checkpoint blockade inhibitors that have been recently investigated in glioblastoma. Current clinical trials and previous clinical trial findings are discussed, shedding light on novel strategies to overcome various limitations and challenges.
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Affiliation(s)
- Boyang Yuan
- Department of Neurosurgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, China
| | - Guoqing Wang
- Department of Neurosurgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, China
| | - Xin Tang
- Department of Neurosurgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, China
| | - Aiping Tong
- State Key Laboratory of Biotherapy, West China Medical School, Sichuan University, Chengdu, Sichuan Province, China
| | - Liangxue Zhou
- Department of Neurosurgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, China
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25
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Augustin RC, Leone RD, Naing A, Fong L, Bao R, Luke JJ. Next steps for clinical translation of adenosine pathway inhibition in cancer immunotherapy. J Immunother Cancer 2022; 10:jitc-2021-004089. [PMID: 35135866 PMCID: PMC8830302 DOI: 10.1136/jitc-2021-004089] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/12/2022] [Indexed: 12/20/2022] Open
Abstract
Increasing evidence supports targeting the adenosine pathway in immuno-oncology with several clinical programs directed at adenosine A2 receptor (A2AR, A2BR), CD73 and CD39 in development. Through a cyclic-AMP-mediated intracellular cascade, adenosine shifts the cytokine and cellular profile of the tumor microenvironment away from cytotoxic T cell inflammation toward one of immune tolerance. A perpetuating cycle of tumor cell proliferation, tissue injury, dysregulated angiogenesis, and hypoxia promote adenosine accumulation via ATP catabolism. Adenosine receptor (eg, A2AR, A2BR) stimulation of both the innate and adaptive cellular precursors lead to immunosuppressive phenotypic differentiation. Preclinical work in various tumor models with adenosine receptor inhibition has demonstrated restoration of immune cell function and tumor regression. Given the broad activity but known limitations of anti-programmed cell death protein (PD1) therapy and other checkpoint inhibitors, ongoing studies have sought to augment the successful outcomes of anti-PD1 therapy with combinatorial approaches, particularly adenosine signaling blockade. Preliminary data have demonstrated an optimal safety profile and enhanced overall response rates in several early phase clinical trials with A2AR and more recently CD73 inhibitors. However, beneficial outcomes for both monotherapy and combinations have been mostly lower than expected based on preclinical studies, indicating a need for more nuanced patient selection or biomarker integration that might predict and optimize patient outcomes. In the context of known immuno-oncology biomarkers such as tumor mutational burden and interferon-associated gene expression, a comparison of adenosine-related gene signatures associated with clinical response indicates an underlying biology related to immunosuppression, angiogenesis, and T cell inflammation. Importantly, though, adenosine associated gene expression may point to a unique intratumoral phenotype independent from IFN-γ related pathways. Here, we discuss the cellular and molecular mechanisms of adenosine-mediated immunosuppression, preclinical investigation of adenosine signaling blockade, recent response data from clinical trials with A2AR, CD73, CD39 and PD1/L1 inhibitors, and ongoing development of predictive gene signatures to enhance combinatorial immune-based therapies.
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Affiliation(s)
- Ryan C Augustin
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Robert D Leone
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Aung Naing
- Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Lawrence Fong
- Department of Medicine and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, USA
| | - Riyue Bao
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.,UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
| | - Jason J Luke
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA .,UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
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26
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Nonaka K, Saio M, Umemura N, Kikuchi A, Takahashi T, Osada S, Yoshida K. Th1 polarization in the tumor microenvironment upregulates the myeloid-derived suppressor-like function of macrophages. Cell Immunol 2021; 369:104437. [PMID: 34530344 DOI: 10.1016/j.cellimm.2021.104437] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 08/10/2021] [Accepted: 08/29/2021] [Indexed: 10/20/2022]
Abstract
Here, we investigated the effect of Th1 polarization in the tumor microenvironment (TME) on tumor-associated macrophage (TAM) maturation and activation. In our immunotherapy mouse model, with a Th1-dominant TME, tumors regressed in all cases, with complete regression in 80% of the cases. Monocyte-derived dendritic cells and activated CD4+ and CD8+T-cells increased in the tumor-draining lymph node, and correlated with each other in the therapeutic model. However, the cytotoxicity of tumor-infiltrating CD8+T-cells was slightly inhibited, whereas the number of T-cells significantly increased. Moreover, the number of TAMs increased; their maturation was inhibited; and nitrotyrosine (NT) production, as well as iNOS and arginase I expression, was increased, suggestive of the myeloid-derived suppressor cell-like immunosuppressive function of TAMs. IFN-γ knockout in the therapeutic model decreased NT production and induced macrophage maturation. Hence, Th1 polarization in the IFN-γ-dominant condition induces T-cell immune responses; however, it also enhances the immunosuppressive activity of TAMs.
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Affiliation(s)
- Kenichi Nonaka
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Yanagido 1-1 Gifu City 501-1194, Japan.
| | - Masanao Saio
- Laboratory of Histopathology and Cytopathology, Department of Laboratory Sciences, Gunma University Graduate School of Health Science, 3 Chome 39-15, Showacho Maebashi City 371-8511, Japan
| | - Naoki Umemura
- Department of Oral and Maxillofacial Sciences, Gifu University Graduate School of Medicine, Yanagido 1-1, Gifu City 501-1194, Japan
| | - Arizumi Kikuchi
- Daiyukai Research Institute for Medical Science, Aza Nijikkenya 25, Nishiazai Azai Cho 491-0113, Japan
| | - Takao Takahashi
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Yanagido 1-1 Gifu City 501-1194, Japan
| | - Shinji Osada
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Yanagido 1-1 Gifu City 501-1194, Japan
| | - Kazuhiro Yoshida
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Yanagido 1-1 Gifu City 501-1194, Japan
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27
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Zahran AM, Shibl A, Rayan A, Mohamed MAEH, Osman AMM, Saad K, Mahmoud KH, Ghandour AMA, Elsayh KI, El-Badawy O. Increase in polymorphonuclear myeloid-derived suppressor cells and regulatory T-cells in children with B-cell acute lymphoblastic leukemia. Sci Rep 2021; 11:15039. [PMID: 34294814 PMCID: PMC8298505 DOI: 10.1038/s41598-021-94469-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Accepted: 07/07/2021] [Indexed: 02/08/2023] Open
Abstract
Our study aimed to evaluate the levels of MDSCs and Tregs in pediatric B-cell acute lymphoblastic leukemia (B-ALL), their relation to patients' clinical and laboratory features, and the impact of these cells on the induction response. This study included 31 pediatric B-ALL patients and 27 healthy controls. All patients were treated according to the protocols of the modified St. Jude Children's Research Hospital total therapy study XIIIB for ALL. Levels of MDSCs and Tregs were analyzed using flow cytometry. We observed a reduction in the levels of CD4 + T-cells and an increase in both the polymorphonuclear MDSCs (PMN-MDSCs) and Tregs. The frequencies of PMN-MDSCs and Tregs were directly related to the levels of peripheral and bone marrow blast cells and CD34 + cells. Complete postinduction remission was associated with reduced percentages of PMN-MDSCs and Tregs, with the level of PMN-MDCs in this subpopulation approaching that of healthy controls. PMN-MDSCs and Tregs jointly play a critical role in maintaining an immune-suppressive state suitable for B-ALL tumor progression. Thereby, they could be independent predictors of B-ALL progress, and finely targeting both PMN-MDSCs and Tregs may be a promising approach for the treatment of B-ALL.
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Affiliation(s)
- Asmaa M Zahran
- Department of Clinical Pathology, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
| | - Azza Shibl
- Pediatric Oncology Department, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
| | - Amal Rayan
- Clinical Oncology Department, Faculty of Medicine, Assiut University, Assiut, 71516, Egypt
| | | | - Amira M M Osman
- Pediatric Oncology Department, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
| | - Khaled Saad
- Pediatric Department, Faculty of Medicine, Assiut University, Assiut, Egypt.
| | | | - Aliaa M A Ghandour
- Medical Microbiology and Immunology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Khalid I Elsayh
- Pediatric Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Omnia El-Badawy
- Medical Microbiology and Immunology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
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28
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Al-Rashed F, Sindhu S, Al Madhoun A, Ahmad Z, AlMekhled D, Azim R, Al-Kandari S, Wahid MAA, Al-Mulla F, Ahmad R. Elevated resting heart rate as a predictor of inflammation and cardiovascular risk in healthy obese individuals. Sci Rep 2021; 11:13883. [PMID: 34230580 PMCID: PMC8260607 DOI: 10.1038/s41598-021-93449-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 06/18/2021] [Indexed: 02/06/2023] Open
Abstract
The role of leukocyte inflammatory markers and toll like receptors (TLRs)2/4 in pathologies associated with elevated resting heart rate (RHR) levels in healthy obese (HO) individuals is not well elucidated. Herein, we investigated the relationship of RHR with expression of leukocyte-inflammatory markers and TLRs in HO individuals. 58-obese and 57-lean participants with no history of a major medical condition, were recruited in this study. In HO individuals, the elevated-RHR correlated positively with diastolic blood pressure, cholesterol, pro-inflammatory monocytes CD11b+CD11c+CD206- phenotype (r = 0.52, P = 0.0003) as well as with activated T cells CD8+HLA-DR+ phenotype (r = 0.27, P = 0.039). No association was found between RHR and the percentage of CD16+CD11b+ neutrophils. Interestingly, elevated RHR positively correlated with cells expressing TLR4 and TLR2 (CD14+TLR4+, r = 0.51, P ≤ 0.0001; and CD14+TLR2+, r = 0.42, P = 0.001). TLR4+ expressing cells also associated positively with the plasma concentrations of proinflammatory or vascular permeability/matrix modulatory markers including TNF-α (r = 0.36, P = 0.005), VEGF (r = 0.47, P = 0.0002), and MMP-9 (r = 0.53, P ≤ 0.0001). Multiple regression revealed that RHR is independently associated with CD14+TLR4+ monocytes and VEGF. We conclude that in HO individuals, increased CD14+TLR4+ monocytes and circulatory VEGF levels associated independently with RHR, implying that RHR monitoring could be used as a non-invasive clinical indicator to identify healthy obese individuals at an increased risk of developing inflammation and cardiovascular disease.
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Affiliation(s)
- Fatema Al-Rashed
- Immunology and Microbiology Department, Dasman Diabetes Institute, Al-Soor Street, P.O. Box 1180, 15462, Dasman, Kuwait
| | - Sardar Sindhu
- Animal and Imaging Core Facility, Dasman Diabetes Institute, Dasman, Kuwait
| | - Ashraf Al Madhoun
- Animal and Imaging Core Facility, Dasman Diabetes Institute, Dasman, Kuwait
| | - Zunair Ahmad
- Royal College of Surgeons in Ireland, Busaiteen, Bahrain
| | - Dawood AlMekhled
- School of Biomedical Sciences, Monash University, Melbourne, Australia
| | - Rafaat Azim
- Royal College of Surgeons in Ireland, Busaiteen, Bahrain
| | - Sarah Al-Kandari
- Immunology and Microbiology Department, Dasman Diabetes Institute, Al-Soor Street, P.O. Box 1180, 15462, Dasman, Kuwait
| | | | - Fahd Al-Mulla
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Dasman, Kuwait
| | - Rasheed Ahmad
- Immunology and Microbiology Department, Dasman Diabetes Institute, Al-Soor Street, P.O. Box 1180, 15462, Dasman, Kuwait.
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Zhang Q, Wang J, Yao X, Wu S, Tian W, Gan C, Wan X, You C, Hu F, Zhang S, Zhang H, Zhao K, Shu K, Lei T. Programmed Cell Death 10 Mediated CXCL2-CXCR2 Signaling in Regulating Tumor-Associated Microglia/Macrophages Recruitment in Glioblastoma. Front Immunol 2021; 12:637053. [PMID: 34108959 PMCID: PMC8182060 DOI: 10.3389/fimmu.2021.637053] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 05/06/2021] [Indexed: 12/03/2022] Open
Abstract
Background Programmed cell death 10 (PDCD10) plays a crucial role in regulating tumor phenotyping, especially in glioblastoma (GBM). Glioma-associated microglia/macrophages (GAMs) in tumor pathological microenvironment contribute to GBM progression. We previously found that the infiltration of GAMs was associated with PDCD10 expression in GBM patients. The present study aims to further explore the regulation of PDCD10 on GAMs in GBM. Methods Overexpression of PDCD10 in human- and murine-GBM cells was established by lentiviral transduction. Cell behaviors and polarization of primary microglia, microglia- and macrophage-like cells were investigated through indirect co-culture with GBM cells in vitro respectively. The PDCD10-induced release of chemokines was identified by a chemokine protein array. The cross-talk between GBM and microglia as well as macrophages was further studied using selective antagonist SB225002. Finally, an orthotopic homograft mouse model was employed to verify the results of in vitro experiments. Results Indirect co-culture with PDCD10-overexpressed GBM cells promoted proliferation and migration of microglia- and macrophage-like cells, and stimulated pro-tumorigenic polarization of primary microglia, microglia- and macrophage-like cells. Pdcd10-upregulated GBM cells triggered a nearly 6-fold increase of CXC motif chemokine ligand 2 (CXCL2) release, which in turn activated CXC chemokine receptor 2 (CXCR2) and downstream Erk1/2 and Akt signaling in primary microglia, microglia- and macrophage-like cells. The blockage of CXCR2 signaling with specific inhibitor (SB225002) abolished microglia- and macrophage-like cell migration induced by PDCD10-upregulated GBM cells. Moreover, Pdcd10-upregulated GL261 cells promoted GAMs recruitment and tumor growth in vivo. Conclusion Our study demonstrates that overexpression of PDCD10 in GBM recruits and activates microglia/macrophages, which in turn promotes tumor progression. CXCL2-CXCR2 signaling mediated by PDCD10 is potentially involved in the crosstalk between GBM cells and GAMs.
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Affiliation(s)
- Quan Zhang
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Junwen Wang
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaolong Yao
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Neurosurgery, The Third People's Hospital of Hubei Province, Wuhan, China
| | - Sisi Wu
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weidong Tian
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Neurosurgery, First Affiliated Hospital of Medical College, Shihezi University, Xinjiang, China
| | - Chao Gan
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xueyan Wan
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chao You
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Hu
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Suojun Zhang
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huaqiu Zhang
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kai Zhao
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kai Shu
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ting Lei
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Hegde S, Leader AM, Merad M. MDSC: Markers, development, states, and unaddressed complexity. Immunity 2021; 54:875-884. [PMID: 33979585 DOI: 10.1016/j.immuni.2021.04.004] [Citation(s) in RCA: 402] [Impact Index Per Article: 100.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 01/20/2021] [Accepted: 04/08/2021] [Indexed: 12/19/2022]
Abstract
Myeloid-derived suppressor cells (MDSCs) are one of the most discussed biological entities in immunology. While the context and classification of this group of cells has evolved, MDSCs most commonly describe cells arising during chronic inflammation, especially late-stage cancers, and are defined by their T cell immunosuppressive functions. This MDSC concept has helped explain myeloid phenomena associated with disease outcome, but currently lacks clear definitions and a unifying framework across pathologies. Here, we propose such a framework to classify MDSCs as discrete cell states based on activation signals in myeloid populations leading to suppressive modes characterized by specific, measurable effects. Developing this level of knowledge of myeloid states across pathological conditions may ultimately transform how disparate diseases are grouped and treated.
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Affiliation(s)
- Samarth Hegde
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Andrew M Leader
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Miriam Merad
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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31
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Zhang S, Li X, Zhu L, Ming S, Wang H, Xie J, Ren L, Huang J, Liang D, Xiong L, Wang Y, Zhang D, Gong S, Wu Y, Geng L. CD163 + macrophages suppress T cell response by producing TGF-β in pediatric colorectal polyps. Int Immunopharmacol 2021; 96:107644. [PMID: 33878617 DOI: 10.1016/j.intimp.2021.107644] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 04/02/2021] [Accepted: 04/02/2021] [Indexed: 12/21/2022]
Abstract
The local immune response plays an important role in the pathogenesis of colorectal carcinoma. Patients with colorectal polyps are at increased risk of colorectal cancer. However, the immunoregulation of early-stage colorectal polyps remain unknown. In the study, 202 biopsy samples from 80 pediatric patients with colorectal polyps and from 42 normal controls were collected. We found that the number of CD4+, CD8+T cells and CD19+B cells were reduced, whereas CD68+macrophages (Mϕ) were increased in colorectal polyps compared to the distal normal tissue from the same patients and the tissue from healthy donors. The frequency of Mϕwas negatively correlated with the number of CD4+ and CD8+T cells but not CD19+B cells in colorectal polyps. We further identified that CD163 was highly expressed on Mϕϕ from colorectal polyps compared to those from normal controls. Furthermore, real-time PCR revealed that TGF-β, but not IL-10 and IL-4, was increased in colorectal polyps. Immunofluorescence and flow cytometry showed that TGF-β was predominantly produced by CD163+Mϕ. In vitro experiments demonstrated that the supernatant from cultured polyps induced CD163 expression and TGF-β production in blood-derived Mϕ. A co-culture experiment revealed that purified Mϕ from colorectal polyps suppressed T cell proliferation. Based on these results, we hypothesized that abundant CD163+Mϕ may promote the progression of colorectal polyps by inhibiting the local T cell response through TGF-β production.
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Affiliation(s)
- Shunxian Zhang
- Department of Gastroenterology, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Xiaoqin Li
- Department of Gastroenterology, Zhengzhou Children's Hospital, Zhengzhou 450000, China
| | - Li Zhu
- Department of Gastroenterology, Children's Hospital of Guiyang, Guiyang 550003, China
| | - Siqi Ming
- Center for Infection and Immunity, Fifth Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangdong 510080, China
| | - Hongli Wang
- Department of Gastroenterology, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Jing Xie
- Department of Gastroenterology, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Lu Ren
- Department of Gastroenterology, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Jing Huang
- Department of Gastroenterology, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Defeng Liang
- Department of Gastroenterology, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Liya Xiong
- Department of Gastroenterology, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Yuesheng Wang
- Department of Gastroenterology, Zhengzhou Children's Hospital, Zhengzhou 450000, China
| | - Dan Zhang
- Department of Gastroenterology, Children's Hospital of Guiyang, Guiyang 550003, China
| | - Sitang Gong
- Department of Gastroenterology, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
| | - Yongjian Wu
- Department of Gastroenterology, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China; Center for Infection and Immunity, Fifth Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangdong 510080, China.
| | - Lanlan Geng
- Department of Gastroenterology, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
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Kimm MA, Klenk C, Alunni-Fabbroni M, Kästle S, Stechele M, Ricke J, Eisenblätter M, Wildgruber M. Tumor-Associated Macrophages-Implications for Molecular Oncology and Imaging. Biomedicines 2021; 9:biomedicines9040374. [PMID: 33918295 PMCID: PMC8066018 DOI: 10.3390/biomedicines9040374] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 03/29/2021] [Accepted: 03/31/2021] [Indexed: 12/21/2022] Open
Abstract
Tumor-associated macrophages (TAMs) represent the largest group of leukocytes within the tumor microenvironment (TME) of solid tumors and orchestrate the composition of anti- as well as pro-tumorigenic factors. This makes TAMs an excellent target for novel cancer therapies. The plasticity of TAMs resulting in varying membrane receptors and expression of intracellular proteins allow the specific characterization of different subsets of TAMs. Those markers similarly allow tracking of TAMs by different means of molecular imaging. This review aims to provides an overview of the origin of tumor-associated macrophages, their polarization in different subtypes, and how characteristic markers of the subtypes can be used as targets for molecular imaging and theranostic approaches.
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Affiliation(s)
- Melanie A. Kimm
- Department of Radiology, University Hospital, LMU Munich, 81377 Munich, Germany; (M.A.K.); (C.K.); (M.A.-F.); (S.K.); (M.S.); (J.R.)
| | - Christopher Klenk
- Department of Radiology, University Hospital, LMU Munich, 81377 Munich, Germany; (M.A.K.); (C.K.); (M.A.-F.); (S.K.); (M.S.); (J.R.)
| | - Marianna Alunni-Fabbroni
- Department of Radiology, University Hospital, LMU Munich, 81377 Munich, Germany; (M.A.K.); (C.K.); (M.A.-F.); (S.K.); (M.S.); (J.R.)
| | - Sophia Kästle
- Department of Radiology, University Hospital, LMU Munich, 81377 Munich, Germany; (M.A.K.); (C.K.); (M.A.-F.); (S.K.); (M.S.); (J.R.)
| | - Matthias Stechele
- Department of Radiology, University Hospital, LMU Munich, 81377 Munich, Germany; (M.A.K.); (C.K.); (M.A.-F.); (S.K.); (M.S.); (J.R.)
| | - Jens Ricke
- Department of Radiology, University Hospital, LMU Munich, 81377 Munich, Germany; (M.A.K.); (C.K.); (M.A.-F.); (S.K.); (M.S.); (J.R.)
| | - Michel Eisenblätter
- Department of Diagnostic and Interventional Radiology, Freiburg University Hospital, 79106 Freiburg, Germany;
| | - Moritz Wildgruber
- Department of Radiology, University Hospital, LMU Munich, 81377 Munich, Germany; (M.A.K.); (C.K.); (M.A.-F.); (S.K.); (M.S.); (J.R.)
- Correspondence: ; Tel.: +49-0-89-4400-76640
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Yu Y, Hu Q, Liu J, Su A, Xu H, Li X, Huang Q, Zhou J, Mariga AM, Yang W. Isolation, purification and identification of immunologically active peptides from Hericium erinaceus. Food Chem Toxicol 2021; 151:112111. [PMID: 33716052 DOI: 10.1016/j.fct.2021.112111] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 02/18/2021] [Accepted: 03/07/2021] [Indexed: 12/21/2022]
Abstract
Biologically active peptides released by proteins are important in regulating immunity. The purpose of this study was to isolate and purify an immunologically active peptide from Hericium erinaceus (H. erinaceus) and to explore its effect on cytokine secretion and differentiation of macrophages. An active peptide with an amino acid sequence, Lys-Ser-Pro-Leu-Tyr (KSPLY) was obtained from H. erinaceus protein by ultrafiltration combined with multistage chromatography separation and identification technology. Subsequently, it was confirmed that the synthetic peptide KSPLY had a good immunomodulatory activity at a concentration of 100 μmol/L and could promote the secretion of NO, IL-1β, IL-6 and TNF-α by macrophages. The effects of KSPLY on M1 macrophages and M2 macrophages were also studied. Results showed that KSPLY inhibited the secretion of NO and IL-6 by M1 macrophages and promoted the tendency of M2 macrophages to transform to M1 macrophages. Therefore, it can be concluded that KSPLY is an effective immunomodulatory peptide that may be beneficial in cancer treatment and human health improvement.
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Affiliation(s)
- Yihan Yu
- Key Laboratory of Grains and Oils Quality Control and Processing, Collaborative Innovation Center for Modern Grain Circulation and Safety, College of Food Science and Engineering, Nanjing University of Finance and Economics, Nanjing, 210023, China
| | - Qiuhui Hu
- Key Laboratory of Grains and Oils Quality Control and Processing, Collaborative Innovation Center for Modern Grain Circulation and Safety, College of Food Science and Engineering, Nanjing University of Finance and Economics, Nanjing, 210023, China
| | - Jianhui Liu
- Key Laboratory of Grains and Oils Quality Control and Processing, Collaborative Innovation Center for Modern Grain Circulation and Safety, College of Food Science and Engineering, Nanjing University of Finance and Economics, Nanjing, 210023, China
| | - Anxiang Su
- Key Laboratory of Grains and Oils Quality Control and Processing, Collaborative Innovation Center for Modern Grain Circulation and Safety, College of Food Science and Engineering, Nanjing University of Finance and Economics, Nanjing, 210023, China
| | - Hui Xu
- Key Laboratory of Grains and Oils Quality Control and Processing, Collaborative Innovation Center for Modern Grain Circulation and Safety, College of Food Science and Engineering, Nanjing University of Finance and Economics, Nanjing, 210023, China
| | - Xiuting Li
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing Technology and Business University, Beijing, 100048, China
| | - Qingrong Huang
- Key Laboratory of Grains and Oils Quality Control and Processing, Collaborative Innovation Center for Modern Grain Circulation and Safety, College of Food Science and Engineering, Nanjing University of Finance and Economics, Nanjing, 210023, China; Food Science, Rutgers University, 65 Dudley Road, New Brunswick, NJ, 08901, United States
| | - Jinlan Zhou
- Key Laboratory of Grains and Oils Quality Control and Processing, Collaborative Innovation Center for Modern Grain Circulation and Safety, College of Food Science and Engineering, Nanjing University of Finance and Economics, Nanjing, 210023, China
| | - Alfred Mugambi Mariga
- School of Agriculture and Food Science, Meru University of Science Technology, P.O. Box, 972-60400, Meru, Kenya
| | - Wenjian Yang
- Key Laboratory of Grains and Oils Quality Control and Processing, Collaborative Innovation Center for Modern Grain Circulation and Safety, College of Food Science and Engineering, Nanjing University of Finance and Economics, Nanjing, 210023, China; Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing Technology and Business University, Beijing, 100048, China.
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Cheng A, Vantucci CE, Krishnan L, Ruehle MA, Kotanchek T, Wood LB, Roy K, Guldberg RE. Early systemic immune biomarkers predict bone regeneration after trauma. Proc Natl Acad Sci U S A 2021; 118:e2017889118. [PMID: 33597299 PMCID: PMC7923361 DOI: 10.1073/pnas.2017889118] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Severe traumatic injuries are a widespread and challenging clinical problem, and yet the factors that drive successful healing and restoration of function are still not well understood. One recently identified risk factor for poor healing outcomes is a dysregulated immune response following injury. In a preclinical model of orthopedic trauma, we demonstrate that distinct systemic immune profiles are correlated with impaired bone regeneration. Most notably, elevated blood levels of myeloid-derived suppressor cells (MDSCs) and the immunosuppressive cytokine interleukin-10 (IL-10) are negatively correlated with functional bone regeneration as early as 1 wk posttreatment. Nonlinear multivariate regression also implicated these two factors as the most influential in predictive computational models. These results support a significant relationship between early systemic immune responses to trauma and subsequent local bone regeneration and indicate that elevated circulating levels of MDSCs and IL-10 may be predictive of poor functional healing outcomes and represent novel targets for immunotherapeutic intervention.
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Affiliation(s)
- Albert Cheng
- George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332
| | - Casey E Vantucci
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332
| | - Laxminarayanan Krishnan
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332
| | - Marissa A Ruehle
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332
| | | | - Levi B Wood
- George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332
| | - Krishnendu Roy
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332
| | - Robert E Guldberg
- George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332;
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332
- Knight Campus for Accelerating Scientific Impact, University of Oregon, Eugene, OR 97403
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Wei J, Chen P, Gupta P, Ott M, Zamler D, Kassab C, Bhat KP, Curran MA, de Groot JF, Heimberger AB. Immune biology of glioma-associated macrophages and microglia: functional and therapeutic implications. Neuro Oncol 2021; 22:180-194. [PMID: 31679017 DOI: 10.1093/neuonc/noz212] [Citation(s) in RCA: 99] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
CNS immune defenses are marshaled and dominated by brain resident macrophages and microglia, which are the innate immune sentinels and frontline host immune barriers against various pathogenic insults. These myeloid lineage cells are the predominant immune population in gliomas and can constitute up to 30-50% of the total cellular composition. Parenchymal microglial cells and recruited monocyte-derived macrophages from the periphery exhibit disease-specific phenotypic characteristics with spatial and temporal distinctions and are heterogeneous subpopulations based on their molecular signatures. A preponderance of myeloid over lymphoid lineage cells during CNS inflammation, including gliomas, is a contrasting feature of brain immunity relative to peripheral immunity. Herein we discuss glioma-associated macrophage and microglia immune biology in the context of their identity, molecular drivers of recruitment, nomenclature and functional paradoxes, therapeutic reprogramming and polarization strategies, relevant challenges, and our perspectives on therapeutic modulation.
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Affiliation(s)
- Jun Wei
- Departments of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Peiwen Chen
- Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Pravesh Gupta
- Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Martina Ott
- Departments of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Daniel Zamler
- Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Cynthia Kassab
- Departments of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Krishna P Bhat
- Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Michael A Curran
- Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - John F de Groot
- Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Amy B Heimberger
- Departments of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
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The role of myeloid-derived suppressor cells in rheumatoid arthritis: An update. Life Sci 2021; 269:119083. [PMID: 33482191 DOI: 10.1016/j.lfs.2021.119083] [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: 11/01/2020] [Revised: 12/27/2020] [Accepted: 01/14/2021] [Indexed: 12/12/2022]
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease that generally affects the joints. In the late stages of the disease, it can be associated with several complications. Although the exact etiology of RA is unknown, various studies have been performed to understand better the immunological mechanisms involved in the pathogenesis of RA. At the onset of the disease, various immune cells migrate to the joints and increase the recruitment of immune cells to the joints by several immunological mediators such as cytokines and chemokines. The function of specific immune cells in RA is well-established. The shift of immune responses to Th1 or Th17 is one of the most essential factors in the development of RA. Myeloid-derived suppressor cells (MDSCs), as a heterogeneous population of myeloid cells, play a regulatory role in the immune system that inhibits T cell activity through several mechanisms. Various studies have been performed on the function of these cells in RA, which in some cases have yielded conflicting results. Therefore, the purpose of this review article is to comprehensively understand the pro-inflammatory and anti-inflammatory functions of MDSCs in the pathogenesis of RA.
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Antonioli L, Fornai M, Pellegrini C, D'Antongiovanni V, Turiello R, Morello S, Haskó G, Blandizzi C. Adenosine Signaling in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1270:145-167. [PMID: 33123998 DOI: 10.1007/978-3-030-47189-7_9] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Adenosine, deriving from ATP released by dying cancer cells and then degradated in the tumor environment by CD39/CD73 enzyme axis, is linked to the generation of an immunosuppressed niche favoring the onset of neoplasia. Signals delivered by extracellular adenosine are detected and transduced by G-protein-coupled cell surface receptors, classified into four subtypes: A1, A2A, A2B, and A3. A critical role of this nucleoside is emerging in the modulation of several immune and nonimmune cells defining the tumor microenvironment, providing novel insights about the development of novel therapeutic strategies aimed at undermining the immune-privileged sites where cancer cells grow and proliferate.
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Affiliation(s)
- Luca Antonioli
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
| | - Matteo Fornai
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | | | - Roberta Turiello
- Department of Pharmacy, University of Salerno, Fisciano, Italy.,PhD Program in Drug discovery and Development, Department of Pharmacy, University of Salerno, Fisciano, Italy
| | - Silvana Morello
- Department of Pharmacy, University of Salerno, Fisciano, Italy
| | - György Haskó
- Department of Anesthesiology, Columbia University, New York, NY, USA
| | - Corrado Blandizzi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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38
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Barouni RM, Musiu C, Bronte V, Ugel S, Canè S. Phenotypical Characterization and Isolation of Tumor-Derived Mouse Myeloid-Derived Suppressor Cells. Methods Mol Biol 2021; 2236:29-42. [PMID: 33237538 DOI: 10.1007/978-1-0716-1060-2_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/27/2024]
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous cell population composed of mature and immature cells of myeloid origin that play a major role in tumor progression by inhibiting the antitumor immune responses mediated by T cells. In this chapter, we describe protocols for isolation, phenotypical and functional evaluation of MDSCs isolated from mouse tumors, with the aim at unifying and standardizing protocols set up by different laboratories.
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Affiliation(s)
- Roza Maria Barouni
- Department of Medicine, Section of Immunology, University of Verona, Verona, Italy
| | - Chiara Musiu
- Department of Medicine, Section of Immunology, University of Verona, Verona, Italy
| | - Vincenzo Bronte
- Department of Medicine, Section of Immunology, University of Verona, Verona, Italy.
| | - Stefano Ugel
- Department of Medicine, Section of Immunology, University of Verona, Verona, Italy
| | - Stefania Canè
- Department of Medicine, Section of Immunology, University of Verona, Verona, Italy
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39
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Distinction of Microglia and Macrophages in Glioblastoma: Close Relatives, Different Tasks? Int J Mol Sci 2020; 22:ijms22010194. [PMID: 33375505 PMCID: PMC7794706 DOI: 10.3390/ijms22010194] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 12/23/2020] [Accepted: 12/24/2020] [Indexed: 12/11/2022] Open
Abstract
For decades, it has been known that the tumor microenvironment is significant for glioma progression, namely the infiltration of myeloid cells like microglia and macrophages. Hence, these cell types and their specific tasks in tumor progression are subject to ongoing research. However, the distribution of the brain resident microglia and the peripheral macrophages within the tumor tissue and their functional activity are highly debated. Results depend on the method used to discriminate between microglia and macrophages, whereby this specification is already difficult due to limited options to distinguish between these both cell populations that show mostly the same surface markers and morphology. Moreover, there are indications about various functions of microglia and macrophages but again varying on the method of discrimination. In our review, we summarize the current literature to determine which methods have been applied to differentiate the brain resident microglia from tumor-infiltrated macrophages. Furthermore, we compiled data about the proportion of microglia and macrophages in glioma tissues and ascertained if pro- or anti-tumoral effects could be allocated to one or the other myeloid cell population. Recent research made tremendous efforts to distinguish microglia from recruited macrophages. For future studies, it could be essential to verify which role these cells play in brain tumor pathology to proceed with novel immunotherapeutic strategies.
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40
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De Leo A, Ugolini A, Veglia F. Myeloid Cells in Glioblastoma Microenvironment. Cells 2020; 10:E18. [PMID: 33374253 PMCID: PMC7824606 DOI: 10.3390/cells10010018] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 12/21/2020] [Accepted: 12/22/2020] [Indexed: 12/21/2022] Open
Abstract
Glioblastoma (GBM) is the most aggressive, malignant primary brain tumor in adults. GBM is notoriously resistant to immunotherapy mainly due to its unique immune microenvironment. High dimensional data analysis reveals the extensive heterogeneity of immune components making up the GBM microenvironment. Myeloid cells are the most predominant contributors to the GBM microenvironment; these cells are critical regulators of immune and therapeutic responses to GBM. Here, we will review the most recent advances on the characteristics and functions of different populations of myeloid cells in GBM, including bone marrow-derived macrophages, microglia, myeloid-derived suppressor cells, dendritic cells, and neutrophils. Epigenetic, metabolic, and phenotypic peculiarities of microglia and bone marrow-derived macrophages will also be assessed. The final goal of this review will be to provide new insights into novel therapeutic approaches for specific targeting of myeloid cells to improve the efficacy of current treatments in GBM patients.
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Affiliation(s)
- Alessandra De Leo
- Department of Immuno-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612-9416, USA; (A.D.L.); (A.U.)
| | - Alessio Ugolini
- Department of Immuno-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612-9416, USA; (A.D.L.); (A.U.)
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Filippo Veglia
- Department of Immuno-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612-9416, USA; (A.D.L.); (A.U.)
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41
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Monocytic and granulocytic myeloid-derived suppressor cell plasticity and differentiation are organ-specific. Oncogene 2020; 40:693-704. [PMID: 33230244 DOI: 10.1038/s41388-020-01559-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 10/22/2020] [Accepted: 11/04/2020] [Indexed: 12/11/2022]
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that proliferate in the setting of cancer and have potent immunosuppressive functions hindering anti-tumor immunity. Here we establish that the immunologic landscape and tumor microenvironments (TME) vary between different organs which discretely shape MDSC repertoires. We found that pSTAT3 signaling exerts a dominant effect on MDSC programming in liver metastasis (LM). In contrast, in lung metastasis (LuM), MDSC programming is driven mainly by pSTAT5. Adoptive transfer of LM-MDSC into LuM resulted in a shift from pSTAT3 signaling to pSTAT5, in association with an overall shift toward lung MDSC programming. A shift from more immunosuppressive M-MDSC to G-MDSC, along with enhanced differentiation of MDSCs into pro-inflammatory M1 macrophages in LuM, indicated that MDSC plasticity and differentiation patterns are environmentally dependent. Using mass spectroscopy, we confirmed that LM-MDSCs showed enhanced expression of key proliferation pathway markers. This confirmed that liver-specific MDSC programing was comprehensive but reversible, implying that therapeutic targeting of LM-MDSC could prime the TME in a favorable manner. Our data suggest that MDSC programming in response to malignancy is highly dependent on organ-specific conditions and is modifiable.
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Frank AS, Larripa K, Ryu H, Snodgrass RG, Röblitz S. Bifurcation and sensitivity analysis reveal key drivers of multistability in a model of macrophage polarization. J Theor Biol 2020; 509:110511. [PMID: 33045246 DOI: 10.1016/j.jtbi.2020.110511] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 09/24/2020] [Accepted: 10/01/2020] [Indexed: 12/13/2022]
Abstract
In this paper, we present and analyze a mathematical model for polarization of a single macrophage which, despite its simplicity, exhibits complex dynamics in terms of multistability. In particular, we demonstrate that an asymmetry in the regulatory mechanisms and parameter values is important for observing multiple phenotypes. Bifurcation and sensitivity analyses show that external signaling cues are necessary for macrophage commitment and emergence to a phenotype, but that the intrinsic macrophage pathways are equally important. Based on our numerical results, we formulate hypotheses that could be further investigated by laboratory experiments to deepen our understanding of macrophage polarization.
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Affiliation(s)
- Anna S Frank
- Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway.
| | - Kamila Larripa
- Department of Mathematics, Humboldt State University, Arcata, CA, USA.
| | - Hwayeon Ryu
- Department of Mathematics and Statistics, Elon University, Elon, NC, USA.
| | - Ryan G Snodgrass
- Institute of Biochemistry, Goethe-University, Frankfurt, Germany.
| | - Susanna Röblitz
- Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway.
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43
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Davidov V, Jensen G, Mai S, Chen SH, Pan PY. Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment. Front Immunol 2020; 11:1842. [PMID: 32983100 PMCID: PMC7492293 DOI: 10.3389/fimmu.2020.01842] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 07/09/2020] [Indexed: 12/30/2022] Open
Abstract
Tumor-mediated regulation of the host immune system involves an intricate signaling network that results in the tumor's inherent survival benefit. Myeloid cells are central in orchestrating the mechanisms by which tumors escape immune detection and continue their proliferative programming. Myeloid cell activation has historically been classified using a dichotomous system of classical (M1-like) and alternative (M2-like) states, defining general pro- and anti-inflammatory functions, respectively. Explosions in bioinformatics analyses have rapidly expanded the definitions of myeloid cell pro- and anti-inflammatory states with different combinations of tissue- and disease-specific phenotypic and functional markers. These new definitions have allowed researchers to target specific subsets of disease-propagating myeloid cells in order to modify or arrest the natural progression of the associated disease, especially in the context of tumor-immune interactions. Here, we discuss the myeloid cell contribution to solid tumor initiation and maintenance, and strategies to reprogram their phenotypic and functional fate, thereby disabling the network that benefits tumor survival.
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Affiliation(s)
- Vitaliy Davidov
- Texas A&M College of Medicine, Bryan, TX, United States.,Center for Immunotherapy Research, Cancer Center of Excellence, Houston Methodist Research Institute, Houston, TX, United States
| | - Garrett Jensen
- Texas A&M College of Medicine, Bryan, TX, United States.,Center for Immunotherapy Research, Cancer Center of Excellence, Houston Methodist Research Institute, Houston, TX, United States
| | - Sunny Mai
- Center for Immunotherapy Research, Cancer Center of Excellence, Houston Methodist Research Institute, Houston, TX, United States
| | - Shu-Hsia Chen
- Texas A&M College of Medicine, Bryan, TX, United States.,Center for Immunotherapy Research, Cancer Center of Excellence, Houston Methodist Research Institute, Houston, TX, United States
| | - Ping-Ying Pan
- Texas A&M College of Medicine, Bryan, TX, United States.,Center for Immunotherapy Research, Cancer Center of Excellence, Houston Methodist Research Institute, Houston, TX, United States
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44
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Scheurlen KM, Billeter AT, O'Brien SJ, Galandiuk S. Metabolic dysfunction and early-onset colorectal cancer - how macrophages build the bridge. Cancer Med 2020; 9:6679-6693. [PMID: 33624450 PMCID: PMC7520341 DOI: 10.1002/cam4.3315] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 06/26/2020] [Indexed: 12/12/2022] Open
Abstract
Background The incidence of colorectal cancer (CRC) among patients <50 years of age has increased dramatically over the last decades. At the same time, the growing proportion of obese children and adolescents and the increasing proportion of young and obese patients with CRC suggests an association between metabolic dysfunction and carcinogenesis. Tumor‐associated macrophages (TAMs) are able to orchestrate tumor promoting and suppressing mechanisms in CRC. The aim of this review was to discuss the different roles of TAMs in CRC and their phenotype‐specific metabolic pathways to identify potential new targets for CRC treatment. Methods A literature search was performed using PubMed, Cochrane and Embase to identify studies on TAMs and their metabolism in CRC. The following search terms were used in various combinations: (obesity OR adiposity OR obese) AND (macrophage OR polarization OR macrophage metabolism) AND ((colon cancer*) OR (colon carcinoma) OR (colonic tumor*) OR (colonic neoplasm[MeSH]) OR (rectal cancer*) OR (rectal carcinoma) OR (rectal tumor*) OR (rectal neoplasm[MeSH]) OR (colorectal cancer*) OR (colorectal carcinoma) OR (colorectal tumor*) OR (colorectal neoplasm[MeSH])). Studies including data on the phenotype and metabolism of TAMs in CRC were analyzed. Results Evidence for the prognostic utility of macrophage markers in CRC is currently evolving, with a particular role of stage‐dependent cellular metabolism profiles of TAMs. Itaconate is one of the metabolites produced by proinflammatory subtypes of TAMs and it is known to have tumor promoting effects. Metabolic pathways that are involved in macrophage activation and reprogramming play a role in a chronic inflammatory setting, consequently affecting the onset and development of CRC. Conclusions Tumor‐promoting metabolites, such as itaconate, are directly regulating these mechanisms, thereby triggering carcinogenesis. Metabolic reprogramming in TAMs can build a bridge between metabolic dysfunction and the onset and progression of CRC through inflammatory pathways, particularly in younger patients with early‐onset CRC.
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Affiliation(s)
- Katharina M Scheurlen
- Price Institute of Surgical Research, Department of Surgery, University of Louisville, Louisville, KY, USA
| | - Adrian T Billeter
- Department of General, Visceral, and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Baden-Wuerttemberg, Germany
| | - Stephen J O'Brien
- Price Institute of Surgical Research, Department of Surgery, University of Louisville, Louisville, KY, USA
| | - Susan Galandiuk
- Price Institute of Surgical Research, Department of Surgery, University of Louisville, Louisville, KY, USA
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45
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DeCordova S, Shastri A, Tsolaki AG, Yasmin H, Klein L, Singh SK, Kishore U. Molecular Heterogeneity and Immunosuppressive Microenvironment in Glioblastoma. Front Immunol 2020; 11:1402. [PMID: 32765498 PMCID: PMC7379131 DOI: 10.3389/fimmu.2020.01402] [Citation(s) in RCA: 199] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 06/01/2020] [Indexed: 12/14/2022] Open
Abstract
Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with a poor prognosis, despite surgical resection combined with radio- and chemotherapy. The major clinical obstacles contributing to poor GBM prognosis are late diagnosis, diffuse infiltration, pseudo-palisading necrosis, microvascular proliferation, and resistance to conventional therapy. These challenges are further compounded by extensive inter- and intra-tumor heterogeneity and the dynamic plasticity of GBM cells. The complex heterogeneous nature of GBM cells is facilitated by the local inflammatory tumor microenvironment, which mostly induces tumor aggressiveness and drug resistance. An immunosuppressive tumor microenvironment of GBM provides multiple pathways for tumor immune evasion. Infiltrating immune cells, mostly tumor-associated macrophages, comprise much of the non-neoplastic population in GBM. Further understanding of the immune microenvironment of GBM is essential to make advances in the development of immunotherapeutics. Recently, whole-genome sequencing, epigenomics and transcriptional profiling have significantly helped improve the prognostic and therapeutic outcomes of GBM patients. Here, we discuss recent genomic advances, the role of innate and adaptive immune mechanisms, and the presence of an established immunosuppressive GBM microenvironment that suppresses and/or prevents the anti-tumor host response.
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Affiliation(s)
- Syreeta DeCordova
- Biosciences, College of Health and Life Sciences, Brunel University London, London, United Kingdom
| | - Abhishek Shastri
- Central and North West London NHS Foundation Trust, London, United Kingdom
| | - Anthony G Tsolaki
- Biosciences, College of Health and Life Sciences, Brunel University London, London, United Kingdom
| | - Hadida Yasmin
- Immunology and Cell Biology Laboratory, Department of Zoology, Cooch Behar Panchanan Barma University, Cooch Behar, India
| | - Lukas Klein
- Department of Gastroenterology and Gastroenterology Oncology, University Medical Centre, Göttingen, Germany
| | - Shiv K Singh
- Department of Gastroenterology and Gastroenterology Oncology, University Medical Centre, Göttingen, Germany
| | - Uday Kishore
- Biosciences, College of Health and Life Sciences, Brunel University London, London, United Kingdom
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Felsenstein M, Blank A, Bungert AD, Mueller A, Ghori A, Kremenetskaia I, Rung O, Broggini T, Turkowski K, Scherschinski L, Raggatz J, Vajkoczy P, Brandenburg S. CCR2 of Tumor Microenvironmental Cells Is a Relevant Modulator of Glioma Biology. Cancers (Basel) 2020; 12:cancers12071882. [PMID: 32668709 PMCID: PMC7408933 DOI: 10.3390/cancers12071882] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Accepted: 07/10/2020] [Indexed: 11/16/2022] Open
Abstract
Glioblastoma multiforme (GBM) shows a high influx of tumor-associated macrophages (TAMs). The CCR2/CCL2 pathway is considered a relevant signal for the recruitment of TAMs and has been suggested as a therapeutic target in malignant gliomas. We found that TAMs of human GBM specimens and of a syngeneic glioma model express CCR2 to varying extents. Using a Ccr2-deficient strain for glioma inoculation revealed a 30% reduction of TAMs intratumorally. This diminished immune cell infiltration occurred with augmented tumor volumes likely based on increased cell proliferation. Remaining TAMs in Ccr2-/- mice showed comparable surface marker expression patterns in comparison to wildtype mice, but expression levels of inflammatory transcription factors (Stat3, Irf7, Cox2) and cytokines (Ifnβ, Il1β, Il12α) were considerably affected. Furthermore, we demonstrated an impact on blood vessel integrity, while vascularization of tumors appeared similar between mouse strains. The higher stability and attenuated leakiness of the tumor vasculature imply improved sustenance of glioma tissue in Ccr2-/- mice. Additionally, despite TAMs residing in the perivascular niche in Ccr2-/- mice, their pro-angiogenic activity was reduced by the downregulation of Vegf. In conclusion, lacking CCR2 solely on tumor microenvironmental cells leads to enhanced tumor progression, whereby high numbers of TAMs infiltrate gliomas independently of the CCR2/CCL2 signal.
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Affiliation(s)
- Matthäus Felsenstein
- Department of Experimental Neurosurgery Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (M.F.); (A.B.); (A.D.B.); (A.M.); (A.G.); (I.K.); (O.R.); (T.B.); (K.T.); (L.S.); (J.R.); (S.B.)
| | - Anne Blank
- Department of Experimental Neurosurgery Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (M.F.); (A.B.); (A.D.B.); (A.M.); (A.G.); (I.K.); (O.R.); (T.B.); (K.T.); (L.S.); (J.R.); (S.B.)
| | - Alexander D. Bungert
- Department of Experimental Neurosurgery Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (M.F.); (A.B.); (A.D.B.); (A.M.); (A.G.); (I.K.); (O.R.); (T.B.); (K.T.); (L.S.); (J.R.); (S.B.)
| | - Annett Mueller
- Department of Experimental Neurosurgery Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (M.F.); (A.B.); (A.D.B.); (A.M.); (A.G.); (I.K.); (O.R.); (T.B.); (K.T.); (L.S.); (J.R.); (S.B.)
| | - Adnan Ghori
- Department of Experimental Neurosurgery Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (M.F.); (A.B.); (A.D.B.); (A.M.); (A.G.); (I.K.); (O.R.); (T.B.); (K.T.); (L.S.); (J.R.); (S.B.)
| | - Irina Kremenetskaia
- Department of Experimental Neurosurgery Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (M.F.); (A.B.); (A.D.B.); (A.M.); (A.G.); (I.K.); (O.R.); (T.B.); (K.T.); (L.S.); (J.R.); (S.B.)
| | - Olga Rung
- Department of Experimental Neurosurgery Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (M.F.); (A.B.); (A.D.B.); (A.M.); (A.G.); (I.K.); (O.R.); (T.B.); (K.T.); (L.S.); (J.R.); (S.B.)
| | - Thomas Broggini
- Department of Experimental Neurosurgery Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (M.F.); (A.B.); (A.D.B.); (A.M.); (A.G.); (I.K.); (O.R.); (T.B.); (K.T.); (L.S.); (J.R.); (S.B.)
| | - Kati Turkowski
- Department of Experimental Neurosurgery Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (M.F.); (A.B.); (A.D.B.); (A.M.); (A.G.); (I.K.); (O.R.); (T.B.); (K.T.); (L.S.); (J.R.); (S.B.)
| | - Lea Scherschinski
- Department of Experimental Neurosurgery Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (M.F.); (A.B.); (A.D.B.); (A.M.); (A.G.); (I.K.); (O.R.); (T.B.); (K.T.); (L.S.); (J.R.); (S.B.)
| | - Jonas Raggatz
- Department of Experimental Neurosurgery Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (M.F.); (A.B.); (A.D.B.); (A.M.); (A.G.); (I.K.); (O.R.); (T.B.); (K.T.); (L.S.); (J.R.); (S.B.)
| | - Peter Vajkoczy
- Department of Experimental Neurosurgery Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (M.F.); (A.B.); (A.D.B.); (A.M.); (A.G.); (I.K.); (O.R.); (T.B.); (K.T.); (L.S.); (J.R.); (S.B.)
- Department of Neurosurgery Charité, Universitätsmedizin Berlin, 10117 Berlin, Germany
- Correspondence: ; Tel.: +49-30-450-560-002
| | - Susan Brandenburg
- Department of Experimental Neurosurgery Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (M.F.); (A.B.); (A.D.B.); (A.M.); (A.G.); (I.K.); (O.R.); (T.B.); (K.T.); (L.S.); (J.R.); (S.B.)
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Metabolomic profiling of tumor-infiltrating macrophages during tumor growth. Cancer Immunol Immunother 2020; 69:2357-2369. [PMID: 32518979 PMCID: PMC7568705 DOI: 10.1007/s00262-020-02622-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 05/22/2020] [Indexed: 12/16/2022]
Abstract
Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) are both key immunosuppressive cells that contribute to tumor growth. Metabolism and immunity of tumors depend on the tumor microenvironment (TME). However, the intracellular metabolism of MDSCs and TAMs during tumor growth remains unclear. Here, we characterized CD11b+ cells isolated from a tumor-bearing mouse model to compare intratumoral TAMs and intrasplenic MDSCs. Intratumoral CD11b+ cells and intrasplenic CD11b+ cells were isolated from tumor-bearing mice at early and late stages (14 and 28 days post-cell transplantation, respectively). The cell number of intrasplenic CD11b+ significantly increased with tumor growth. These cells included neutrophils holding segmented leukocytes or monocytes with an oval nucleus and Gr-1hi IL-4Rαhi cells without immunosuppressive function against CD8 T cells. Thus, these cells were classified as MDSC-like cells (MDSC-LCs). Intratumoral CD11b+ cells included macrophages with a round nucleus and were F4/80hi Gr-1lo IL-4Rαhi cells. Early stage intratumoral CD11b+ cells inhibited CD8 T cells via TNFα. Thus, this cell population was classified as TAMs. Metabolomic analyses of intratumoral TAMs and MDSC-LCs during tumor growth were conducted. Metabolic profiles of intratumoral TAMs showed larger changes in various metabolic pathways, e.g., glycolysis, TCA cycle, and glutamic acid pathways, during tumor growth compared with MDSL-LCs. Our findings demonstrated that intratumoral TAMs showed an immunosuppressive capacity from the early tumor stage and underwent intracellular metabolism changes during tumor growth. These results clarify the intracellular metabolism of TAMs during tumor growth and contribute to our understanding of tumor immunity.
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Wu J, Yang H, Cheng J, Zhang L, Ke Y, Zhu Y, Wang C, Zhang X, Zhen X, Zheng LT. Knockdown of milk-fat globule EGF factor-8 suppresses glioma progression in GL261 glioma cells by repressing microglial M2 polarization. J Cell Physiol 2020; 235:8679-8690. [PMID: 32324268 DOI: 10.1002/jcp.29712] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 03/18/2020] [Accepted: 04/02/2020] [Indexed: 01/02/2023]
Abstract
Tumor-associated microglial cells promote glioma growth, invasion, and chemoresistance by releasing inflammatory factors. Milk fat globule EGF factor 8 protein (MFG-E8), a secreted glycoprotein, is closely related to tissue homeostasis and anti-inflammation. In the present study, we investigated the role of MFG-E8 in microglial polarization and glioma progression in vitro and in vivo. We found that glioma cells secrete comparable amounts of MFG-E8 in culture media to astrocytes. Recombinant MFG-E8 triggered microglia to express the M2 polarization markers, such as arginase-1 (ARG-1), macrophage galactose-type C-type lectin-2 (MGL-2), and macrophage mannose receptor (CD206). Forced expression of MFG-E8 in BV-2 microglia cells not only promoted IL-4-induced M2 polarization but also inhibited lipopolysaccharide (LPS)-induced M1 microglial polarization. Mechanistic studies demonstrated that recombinant MFG-E8 markedly induced signal transducer and activator of transcription 3 (STAT3) phosphorylation, and the STAT3 inhibitor stattic significantly blocked MFG-E8-induced ARG-1 expression. Administration of antibody against MFG-E8 and knockdown of its receptor, integrin β3, significantly attenuated MFG-E8-induced ARG-1 expression. Similarly, knockdown of MFG-E8 also markedly reduced IL-4-induced M2 marker expression and increased LPS-induced M1 marker expression in microglia cells. Moreover, the knockdown of MFG-E8 in GL261 glioma cells inhibited cell proliferation and enhanced chemosensitivity to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), which was likely associated with the downregulation of FAK/AKT activation and STAT3/cyclin D1 signaling. The murine GL261 glioma experimental model demonstrated that knockdown of MFG-E8 significantly reduced tumor size and extended survival times. Additionally, attenuated CD11b+ cell infiltration and reduced CD206+ expression in CD11b+ cells were also observed in an MFG-E8 knockdown GL261 murine glioma model. These results suggested that inhibition of MFG-E8 might hamper the immunosuppressive microenvironment in gliomas and therefore ameliorate tumor progression.
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Affiliation(s)
- Jing Wu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Huicui Yang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Junjie Cheng
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Li Zhang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Youliang Ke
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Yi Zhu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Cheng Wang
- The Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medical University, Suzhou, Jiangsu, China
| | - Xiaohu Zhang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Xuechu Zhen
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Long Tai Zheng
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
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Shan X, Zhang C, Wang Z, Wang K, Wang J, Qiu X, Jiang T, Yang P. Prognostic value of a nine-gene signature in glioma patients based on tumor-associated macrophages expression profiling. Clin Immunol 2020; 216:108430. [PMID: 32325251 DOI: 10.1016/j.clim.2020.108430] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 03/29/2020] [Accepted: 04/17/2020] [Indexed: 12/17/2022]
Abstract
Tumor-associated macrophages (TAMs) are regarded as the most abundantly infiltrating immune cells around the tumor microenvironment in gliomas, which plays an important role in tumorgenesis and immunosuppression. A total of 216 patients diagnosed with primary glioma were obtained from the Chinese Glioma Genome Atlas of which the RNA sequencing data was used as training set. RNA sequencing from the Cancer Genome Atlas was applicated for validation. We found that mesenchymal subtype showed strong positive correlation with macrophage-related genes (MRGs) expression. Survival analysis showed that high expression level of MRG predicted poor prognosis. A TAM-based nine-gene signature was constructed, which divided the samples into high- and low-risk of unfavorable outcome. The result of Cox regression analysis showed that the risk score was an independent prognostic factor in gliomas. Hence, the expression of TAMs was correlated with patient survival. The nine-TAM-related gene signature can predict patient survival efficiently.
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Affiliation(s)
- Xia Shan
- Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, China; Department of Radiotherapy, Beijing Tiantan Hospital, Capital Medical University, China
| | - Chuanbao Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China
| | - Zheng Wang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China
| | - Kuanyu Wang
- Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, China
| | - Jiangfei Wang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China
| | - Xiaoguang Qiu
- Department of Radiotherapy, Beijing Tiantan Hospital, Capital Medical University, China
| | - Tao Jiang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China; Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, China; Center of Brain Tumor, Beijing Institute for Brain Disorder, China; China National Clinical Research Center for Neurological Diseases, China; Chinese Glioma Genome Atlas Network (CGGA), China
| | - Pei Yang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China; Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, China.
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Mechanism of Xu Li's Experiential Prescription for the Treatment of EGFR-Positive NSCLC. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:8787153. [PMID: 32256661 PMCID: PMC7091530 DOI: 10.1155/2020/8787153] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Accepted: 01/18/2020] [Indexed: 02/07/2023]
Abstract
The non-small-cell lung cancer (NSCLC) is the most common lung cancer which seriously threatens the human health. Xu Li's experiential prescription (XLEP) can treat the NSCLC. However, whether XLEP can regulate the autophagy in the EGFR-positive NSCLC still remains unknown. We found that the cellular activity of drug-resistant cells and sensitive cells were all decreased in the TCM group and TCM + Gef group. The expression of autophagy-associated proteins (mTOR and Beclin1-Vps34) in drug-resistant cells was decreased in the TCM group, while the expression of autophagy-associated proteins in sensitive cells was all decreased in the TCM + Gef group. The ratio of M1/M2 macrophages was increased when IL-4-induced RAW264.7 was treated with TCM. TCM treatment promoted the expression of CCL2 and CCL3 while it downregulated the CCL22 level among A549, H1975, and PC9 cells. The expression of TNF-α and IL-6 was increased, and the expression of IL-10 and TGF-β was decreased in IL-4-induced RAW264.7 cells treated with TCM. And, TCM treatment also decreased the expression of Fizz1 and TGM2. In conclusion, this study indicated that XLEP could suppress the proliferation of EGFR-TKI-resistant cancer cells and increase the ratio of M1/M2 macrophages by inhibiting autophagy to treat the drug-resistant EGFR-positive NSCLC.
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