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

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.