Study of the extracellular vesicles secreted by MHC class II expressing melanoma cells.

Melanoma is one of the most aggressive cancers worldwide and the deadliest form of skin cancer whose incidence rate, unfortunately, is increasing rapidly in western populations. Indeed, the aggressive metastatic trend of melanoma is associated to the increase of cellular dissemination and is the consequence of a multistep process involving mutations of survival molecules, inhibition of apoptotic pathways, increase of tumour cells detachment from primary tumour as well as to the interaction between tumour cells and cellular blood components. The Major Histocompatibility Complex (MHC) class II molecules are expressed constitutively in almost 50% of melanoma and although the MHC class II molecules expressed in melanoma cells may directly present tumour antigens to CD4+ T cells and trigger their effector functions, the constitutive MHC class II expression in melanoma is related to a bad prognosis. The MHC class II molecules are signalling receptors whose engagement leads to the activation of several signalling proteins and to the increase of the expression of several kinases as well as the lipid raft localisation of class II molecules, PD-L1 receptor, Integrin and CAM adhesion receptors, FAK, AKT and STAT3 signalling proteins suggesting that the HLA-DR mediated signalling provides a platform useful to frustrate an effective antitumour response and to increase melanoma migration and metastatic dissemination of this cancer. The melanoma cells secrete in their microenvironment extracellular vesicles, that for their nanoscale size, can circulate in advancing tumour front and in distant tissues interacting with immune cells, tumour cells and with different cell types. Indeed, the extracellular vesicles secreted by melanoma cells play a main role in the metastatic progression of melanoma regulating the immune cell functions and modifying the tumour microenvironment. Therefore, in extracellular vesicles secreted by MHC class II stimulated melanoma cells, the increased amount of receptors and signalling proteins, could act in concert to enhance the breakdown and the remodelling of the extracellular matrix, thus enhancing the tumour cell invasion of microenvironment and the metastatic progression of melanoma cells. In particular, our work suggests that the MHC class II mediated signalling plays a new role to promote melanoma progression enhancing, through the extracellular vesicles secreted, the metastatic dissemination of melanoma cells as well as inhibiting the immune response in tumour microenvironment.