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.
This project will be dedicated to the establishment of strategies aimed at improving NK cell homing to BM with the aim of increasing the load of effector cells targeting MM.
Current adoptive NK cell therapy approaches are mostly based on the infusion of expanded or activated with cytokines in vitro NK cells. Among the various cytokines studied for in vitro activation of NK cells, IL-15 is the most attractive one since it does not stimulate competing cells with immunosuppressive properties, such as T regulatory cells, one important effect observed with IL-2 treatment. However, to obtain significant antitumor reactivity and increased in vivo survival of the transferred cells, very high doses of IL-15 are required, leading to adverse side effects related to the toxicity. This raises the importance of the use of in vitro preactivated NK cells to be used for adoptive immunotherapy and of the establishment of the better experimental condition to increase their persistence and expansion in vivo. As for multiple myeloma, a fundamental problem is the reduced NK cell recruitment to the tumor growth, leading to a failure of immune surveillance. This may be partly responsible of extensive suppression of the cytotoxic function of these effector cells in the tumor microenvironment. Furthermore, during disease progression, MM cells up-regulate expression of the ligands of inhibitory receptors, including the ligand od PD-1, PD-L1, likely contributing to immune escape. The correct homing of NK cells used for adoptive immunotherapy into the tumor site is a prime assumption for their ability to induce tumor regression; so the exploitation of strategies that interest chemokine receptors, such as CXCR3, to improve migration of NK cells could be fundamental. Overall, our results will help to design therapeutic strategies aimed at promoting NK cell-based anti-MM immune response by proposing strategies to overcome inhibition of migration.