Ricerc@Sapienza

Natural Killer (NK) cells are the prototypical cytotoxic innate lymphocytes and play a pivotal role in the immune response against cancer cells. Multiple myeloma (MM) is an incurable hematopoietic neoplasia characterized by clonal growth of malignant plasma cells in bone marrow (BM). Current protocols based on adoptive NK cell therapy represents a promising therapeutic strategy in MM patients. However, a suppressive MM microenvironment limits its effectiveness. We have identified the ligands of the chemokine receptor CXCR3 as critical factors reducing localization of functional NK cell subsets in BM during MM. Our observations in a mouse model suggested a prognostic role of CXCL10 in MM patients that was recently confirmed. In fact, survival of patients was correlated inversely with high serum levels of CXCL10. Stratifying patients based on CXCL10 expression levels, we observed marked changes of NK cell subset distribution and expression of the NCR NKp30 in the BM. We hypothesize that CXCR3 activation promotes mobilization of effector NK cells from BM, thus reducing NK cell capacity to interact with MM cells. Thus, the anti-tumor potential of NK cell-based adoptive therapy could be increased by inhibiting CXCR3 expression/function and enhancing CXCR4 activation. These phenomena will allow a better homing of activated/expanded NK cells to BM into MM microenvironmental niches.