Extracellular vesicles secreted by MHC class II expressing melanoma cells and their role in immune escape and cancer progression.

Melanoma, one of the most widespread cancers in the Western population, is the deadliest form of skin cancer whose incidence rate will increase this year, making melanoma the second most diagnosed cancer. Melanoma cells secrete in their microenvironment extracellular vesicles that, for their nanoscale size, can circulate in advancing tumor front and in distant tissues, interacting with immune cells and different cell types as mediators of metastasis. Indeed, the metastatic progression of melanoma is associated with the expression of Major Histocompatibility Complex (MHC) class II molecules that are constitutively expressed in almost 50% of melanoma. Although MHC class II molecules expressed in melanoma cells may present tumor antigens to CD4+ T cells and trigger their effector functions, the constitutive MHC class II expression in melanoma is related to a bad prognosis. Therefore, the aim of our work was to understand the consequences of MHC class II-mediated signaling on extracellular vesicles secreted by melanoma cells. Indeed, we showed in extracellular vesicles secreted by class II constitutive expressing melanoma cell lines that the MHC class II-mediated signaling increases the expression of HLA-DR, adhesion receptors, PDL1, and STAT3. Furthermore, through co-culture experiments of PBMCs and extracellular vesicles, we showed that MHC class II-mediated signaling enhances the cytotoxic effects of extracellular vesicles on PBMCs. Indeed, our results suggest that MHC class II-mediated signaling plays a new role in promoting melanoma progression, enhancing, through the extracellular vesicles secreted, the metastatic dissemination of melanoma cells and inhibiting the immune response.