Dataset Information

Immunopeptidomic analyses - HLA Export by Melanoma Cells Decoys Cytotoxic T Cells to Promote Immune Evasion

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 MHC molecules that stimulate CD8+ T cells through their T-cell receptor (TCR), causing T cell dysfunction and apoptosis. Immunopeptidomic and TCR-seq analyses revealed that these melanosomes carry MHC-bound-Tumor-Associate- 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Skin

SUBMITTER: Chen Weller

LAB HEAD: Yardena Samuels

PROVIDER: PXD069094 | Pride | 2026-04-19

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	QEP2_CLE_13602_976_310321.raw	Raw
	QEP2_CLE_13602_977_310321.raw	Raw
	QEP2_CLE_13602_978_310321.raw	Raw
	QEP2_CLE_13602_979_310321.raw	Raw
	QEP2_CLE_13602_980_310321.raw	Raw

Items per page:

1 - 5 of 28

Publications

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

Chemla Yoav Y Itzhaki Orit O Melamed Stav S Weller Chen C Sade Yuval Y Manich Paulee P Reshef Keren K Xenidis Nicolas N Maliah Avishai A Levy Gilad G Parikh Roma R Bartok Osnat O Levy Opal O Tal Itay I Aziel Gal G Nissani Abraham A Yunger Sharon S Likonen Daniela D Kliminsky Vitaly V Golan Tamar T Capron Coralie C Ace Valentina V Levy Ronen R Rasoulouniriana Diana D Eyal Zohar Z Barzilay Yuval Y Balaban Roi R Khateeb Aseel A Khosravi Rami R Grau Amir A Ziv Tamar T Greenberg Polina P Netanely Dvir D Vaknin Hananya H Wu Xunwei X Amitay Yael Y Brenner Ronen R Martínez Gómez Julia María JM Hershkovitz Dov D Yardeni Tal T Zemser-Werner Valentina V Kobiler Oren O Friedmann Yael Y Bassan David D Shamir Ron R Eisenbach Lea L Santana-Magal Nadine N Milyavsky Michael M Eisenberg Galit G Keren Leeat L Cohen Merav M Gur Dvir D Barak Boaz B Lotem Michal M Sprinzak David D Greenberger Shoshana S Fisher David D Besser Michal J MJ Khaled Mehdi M Close Pierre P Shapira Ronnie R Apcher Sebastien S Madi Asaf A Levesque Mitchell P MP Rapino Francesca F Carmi Yaron Y Parikh Shivang S Samuels Yardena Y Levy Carmit C

Cell 20251215 1

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<sup>+</sup> T cells through their T cell receptor (TCR), causing T cell dysfunction and apoptosis. Immunopeptidomic and T cell receptor sequencing (TCR-seq) analy ...[more]

PMID: 41401806

Similar Datasets

Project description:Immune evasion is an important hallmark of cancer ensured by diverse strategies, including immunosuppression and downregulation of antigen presentation. Here, to restore immunogenicity of cancer cells, we employed the minimal gene regulatory network of highly immunogenic type 1 conventional dendritic cells (cDC1) to reprogram cancer cells into professional antigen presenting cells (APCs). We showed that enforced expression of PU.1, IRF8 and BATF3 (PIB) was sufficient to induce cDC1 phenotype in 33 cell lines derived from human and mouse hematological and solid tumors. PIB gradually modified the cancer cell transcriptional and epigenetic program imposing global antigen presentation and cDC1 gene signatures within 9 days. cDC1 reprogramming restored the expression of antigen presentation complexes as well as co-stimulatory molecules at the cell surface, leading to the presentation of endogenous antigens on MHC-I, and to CD8+ T cell mediated killing. Functionally, tumor- APCs acquired the ability to uptake and process exogenous proteins and dead cells, secreted inflammatory cytokines and cross-presented antigens to naïve CD8+ T cells. Importantly, tumor-APCs were efficiently generated at the single cell level from primary cancer cells of 7 solid tumors that presented antigens to memory and naïve T-cells, as well as to activated patient-specific intra-tumoral lymphocytes. Alongside antigen presentation, tumor-APCs harboring TP53, KRAS and PTEN mutations showed impaired tumorigenicity in vitro and in vivo. Finally, using in vivo mouse models of melanoma, we showed that intra-tumoral injection of tumor-APCs promoted lymphoid infiltration, delayed tumor growth and increased survival. The anti-tumor immunity elicited by tumor-APCs was synergistic with immune checkpoint inhibitors enabling tumor eradication. Our approach combines cDC1’s antigen processing and presenting abilities with endogenous generation of tumor antigens and serves as a platform for the development of novel immunotherapies based on endowed antigen presentation in cancer cells.