Chemla et al. demonstrated that melanosomes, large extracellular vesicles secreted by melanoma cells, carry MHC-I molecules as active mediators for immune evasion. Melanosomes present tumor-associated antigens and neoantigens that directly engage CD8+ T cell receptors and compete with tumor cells for TCR binding, diverting antigen recognition away from malignant cells. Melanosome–TCR engagement induced incomplete activation, mitochondrial dysfunction, and apoptosis in CD8+ T cells. Inhibiting melanosome secretion restored CD8+ T cell infiltration and restrained tumor growth in the B16F10 melanoma model.
Contributed by Shishir Pant
ABSTRACT: While melanoma cells often express a high burden of mutated proteins, the infiltration of reactive T cells rarely results in tumor-eradicating immunity. We discovered that large extracellular vesicles, known as melanosomes, secreted by melanoma cells are decorated with major histocompatibility complex (MHC) molecules that stimulate CD8(+) T cells through their T cell receptor (TCR), causing T cell dysfunction and apoptosis. Immunopeptidomic and T cell receptor sequencing (TCR-seq) analyses revealed that these melanosomes carry MHC-bound tumor-associated antigens with higher affinity and immunogenicity, which compete with their tumor cell of origin for direct TCR-MHC interactions. Analysis of biopsies from melanoma patients confirmed that melanosomes trap infiltrating lymphocytes, induce partial activation, and decrease CD8(+) T cell cytotoxicity. Inhibition of melanosome secretion in vivo significantly reduced tumor immune evasion. These findings suggest that MHC export protects melanoma from the cytotoxic effects of T cells. Our study highlights a novel immune evasion mechanism and proposes a therapeutic avenue to enhance tumor immunity.
Author Info: (1) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (2) Department of Human Genetics and Bi
Author Info: (1) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (2) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel; Ella Lemelbaum Institute for Immuno-Oncology and Melanoma, Sheba Medical Center, Ramat Gan 52621, Israel. (3) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (4) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (5) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (6) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (7) Department of Pathology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (8) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (9) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (10) Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel. (11) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (12) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (13) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (14) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (15) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (16) Ella Lemelbaum Institute for Immuno-Oncology and Melanoma, Sheba Medical Center, Ramat Gan 52621, Israel. (17) Ella Lemelbaum Institute for Immuno-Oncology and Melanoma, Sheba Medical Center, Ramat Gan 52621, Israel. (18) Department of Dermatology, Sheba Medical Center, Ramat Gan, Israel. (19) Department of Dermatology, Sheba Medical Center, Ramat Gan, Israel. (20) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (21) Laboratory of Cancer Stemness, GIGA Institute, University of Lige, Lige, Belgium. (22) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (23) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (24) Department of Pathology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (25) Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel. (26) Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel. (27) Department of Clinical Microbiology and Immunology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel. (28) Department of Pathology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (29) Single Cell Genomics Core, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel. (30) Biomedical Core Facility, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. (31) Smoler Proteomics Center, Lokey Interdisciplinary Center for Life Sciences & Engineering, Technion-Israel Institute of Technology, Haifa, Israel. (32) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (33) Blavatnik School of Computer Science and Artificial Intelligence, Tel Aviv University, Tel Aviv, Israel. (34) Institute of Oncology, E. Wolfson Medical Center, Holon, Israel. (35) Department of Dermatology, Massachusetts General Hospital, Boston, MA, USA. (36) Department of Molecular Cell Biology, Weizmann Institute of Science, Tel Aviv, Israel. (37) Institute of Oncology, E. Wolfson Medical Center, Holon, Israel. (38) Laboratory of Cancer Stemness, GIGA Institute, University of Lige, Lige, Belgium. (39) Institute of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. (40) Metabolic Center, Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel. (41) Institute of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. (42) Department of Clinical Microbiology and Immunology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel. (43) Bio-Imaging Unit, Hebrew University, Jerusalem 91904, Israel. (44) Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel. (45) Blavatnik School of Computer Science and Artificial Intelligence, Tel Aviv University, Tel Aviv, Israel. (46) Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel. (47) Department of Pathology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (48) Department of Pathology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (49) Hadassah Cancer Research Institute, Hadassah Hebrew University Hospital, Jerusalem, Israel. (50) Department of Molecular Cell Biology, Weizmann Institute of Science, Tel Aviv, Israel. (51) Department of Clinical Microbiology and Immunology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel. (52) Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel. (53) Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel; The School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel. (54) Hadassah Cancer Research Institute, Hadassah Hebrew University Hospital, Jerusalem, Israel. (55) School of Neurobiology, Biochemistry and Biophysics, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel. (56) Department of Clinical Microbiology and Immunology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel. (57) Department of Dermatology, Massachusetts General Hospital, Boston, MA, USA. (58) Ella Lemelbaum Institute for Immuno-Oncology and Melanoma, Sheba Medical Center, Ramat Gan 52621, Israel; Department of Clinical Microbiology and Immunology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel; Samueli Integrative Pioneering Institute and Davidoff Center, Rabin Medical Center, Petach Tikva, Israel; Felsenstein Cancer Research Center, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel. (59) Gustave Roussy Cancer Campus, INSERM U1015, Universite Paris-Saclay, 114 rue Edouard Vaillant, 94800 Villejuif, France. Electronic address: mehdi.khaled@gustaveroussy.fr. (60) Laboratory of Cancer Signaling, GIGA Institute, University of Lige, Lige, Belgium. Electronic address: pierre.close@uliege.be. (61) Ella Lemelbaum Institute for Immuno-Oncology and Melanoma, Sheba Medical Center, Ramat Gan 52621, Israel. Electronic address: ronnie.shapira@sheba.health.gov.il. (62) Gustave Roussy Cancer Campus, INSERM U1015, Universite Paris-Saclay, 114 rue Edouard Vaillant, 94800 Villejuif, France. Electronic address: sebastien.apcher@gustaveroussy.fr. (63) Department of Pathology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: asafmadi@tauex.tau.ac.il. (64) University of Zurich, Faculty of Medicine, University Hospital of Zurich, Department of Dermatology, Schlieren 8952, Switzerland. Electronic address: mitchell.levesque@usz.ch. (65) Laboratory of Cancer Stemness, GIGA Institute, University of Lige, Lige, Belgium. Electronic address: francesca.rapino@uliege.be. (66) Department of Pathology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: yaroncarmi@gmail.com. (67) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel; Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA. Electronic address: ssparikh@mgh.harvard.edu. (68) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. Electronic address: yardena.samuels@weizmann.ac.il. (69) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: carmitlevy@tauex.tau.ac.il.
