Extracellular vesicles released from melanoma cells constitutively expressing MHC class II promote immune evasion and cancer progression

The metastatic progression of melanoma, a highly immunogenic cancer, is often associated with constitutive expression of major histocompatibility complex (MHC) class II molecules. Their engagement leads to increased expression and activation of signaling proteins, kinases, and adhesion receptors. Melanoma cells release extracellular vesicles (EVs) that are involved in the metastatic progression of melanoma through modifying the tumor microenvironment. Here, we report that MHC class II molecules, when constitutively expressed on melanoma cells, drive the role of EVs in regulating immune cell function, melanoma metastasis, and tumor microenvironment remodeling. In particular, we observed an increased localization of HLA-DRα, CAM receptors, PD-L1, and STAT3 signaling proteins in EVs. Using co-culture experiments, we demonstrate the EV-induced apoptosis of PBMCs, as well as the increased migration of fibroblasts and melanoma cells in response to MHC class II-activated signaling. Overall, these results highlight a complex and dynamic interplay between fibroblasts, tumor cells, and EVs, which, as key mediators of cell communication, establish a paracrine and autocrine signaling circuit crucial for regulating tumor cell and fibroblast migration. Our results demonstrate that MHC class II-activated signaling is critical for melanoma progression, driving enhanced metastatic dissemination and immune evasion via extracellular vesicles in the tumor microenvironment.