Ricerc@Sapienza

Increasing evidence has shown that extracellular vesicles play a relevant role in intercellular communication, thanks to their ability to convey active biological molecules onto target cells. Notably, a number of studies demonstrated that cancer derived-EVs have the capability to modulate both innate and adaptive immune responses thus contributing to influence tumor progression. Natural killer (NK) cells are innate lymphoid cells that play a major role in the immune surveillance against tumors and their activity is regulated through signals derived by a number of NK cell inhibitory and activating receptors as well as cytokines and other soluble factors released in the tumor microenvironment. NKG2D is an activating receptor expressed on the surface of NK cells, CD8+ ¿ß T lymphocytes, ¿¿ T cells, and NKT cells. It recognizes two families of ligands in human: MIC (MICA/B) and the ULBP (ULBP1-6) that are expressed on cell surface as signal of stress, as for example after viral infection or tumor transformation or in response to chemotherapy. Of note, NKG2D ligands (NKG2DLs) can be released in the extracellular milieu through protease-mediated cleavage or by extracellular vesicle (EV) secretion. Focusing on multiple myeloma (MM) as a clinically and biologically relevant model of tumor-NK cell interactions, we found enrichment of EVs expressing MICA in the bone marrow of a cohort of patients. In this project we will investigate the immunomodulatory properties of the NKG2D ligand MICA associated to distinct populations of EVs (i.e exosomes and microvesicles). In sum, understanding the mechanisms by which NKG2D ligand associated to EVs influence the NK cell phenotype and functions can open new possibilities for cancer therapy.