HLA export by melanoma cells decoys cytotoxic T cells to promote immune evasion.

CD8 T cells; HLA-peptidomics; MHC; TCR-seq; extracellular vesicles; immunotherapy; melanoma; melanosomes; tumor microenvironment; tumor-infiltrating lymphocytes; Receptors, Antigen, T-Cell; HLA Antigens; Antigens, Neoplasm; Humans; Animals; Melanosomes/metabolism; Melanosomes/immunology; Receptors, Antigen, T-Cell/metabolism; Receptors, Antigen, T-Cell/immunology; Cell Line, Tumor; Mice; CD8-Positive T-Lymphocytes/immunology; Antigens, Neoplasm/immunology; Antigens, Neoplasm/metabolism; Melanoma/immunology; Melanoma/pathology; Melanoma/metabolism; T-Lymphocytes, Cytotoxic/immunology; Immune Evasion; HLA Antigens/metabolism; HLA Antigens/immunology; Tumor Escape; CD8-Positive T-Lymphocytes; T-Lymphocytes, Cytotoxic; Biochemistry, Genetics and Molecular Biology (all)

Abstract :

[en] 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.

Disciplines :

Immunology & infectious disease

Author, co-author :

Chemla, Yoav ^✱; Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel

Itzhaki, Orit ^✱; 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

Melamed, Stav ^✱; Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel

Weller, Chen ^✱; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel

Sade, Yuval ^✱; Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel

Manich, Paulee ^✱; Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel

Reshef, Keren ^✱; Department of Pathology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel

Xenidis, Nicolas ^✱; Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel

Maliah, Avishai ^✱; Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel

Levy, Gilad; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel

More authors (59 more)

^✱ These authors have contributed equally to this work.

Language :

English

Title :

HLA export by melanoma cells decoys cytotoxic T cells to promote immune evasion.

Publication date :

08 January 2026

Journal title :

Cell

ISSN :

0092-8674

eISSN :

1097-4172

Publisher :

Elsevier B.V., United States

Volume :

189

Issue :

Pages :

233 - 251.e29

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://api.elsevier.com/content/article/PII:S0092867425013169?httpAccept=text/xml

Funders :

Tel Aviv University

Available on ORBi :

since 21 February 2026

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