Intercellular Transfer of CD155 Mediated by Melanoma Extracellular Vesicles Downregulates DNAM-1 Expression on NK Cells

Melanoma is a highly immunogenic cancer, and immunotherapy is the first-line treatment for patients with advanced disease. However, CD155 overexpression in melanoma has been associated with resistance to immunotherapy. Whether CD155 can be transferred from tumour cells via extracellular vesicles (EVs), and how this transfer affects immune responses in melanoma, remains unclear. To investigate melanoma cell transfer of CD155 in vivo, B16F10-WT and B16F10-CD155KO melanoma cells were subcutaneously injected into CD155−/− mice. We show that CD155 is transferred from melanoma cells to several immune cell populations infiltrating the tumour, at least partly through EV secretion and uptake. DNAM-1 expression was significantly reduced on natural killer (NK) cells in B16F10-WT tumours compared with B16F10-CD155KO tumours. We also found that CD155 was enclosed and enriched in different melanoma EV subtypes. Finally, incubation of NK cells with CD155+ melanoma EVs increased cellular CD155 levels and led to downregulation of DNAM-1. In summary, melanoma-derived CD155 is enriched in melanoma EVs and transferred to immune cells, especially NK cells. Moreover, cancer-derived CD155+ EVs increase CD155 expression on NK cells and are associated with reduced DNAM-1 expression.