Natural killer (NK) cells are innate cytotoxic cells that actively prevent neoplastic development, growth, and metastatic dissemination in a process called cancer immunosurveillance. Multiple myeloma (MM) is a hematological disease characterized by the expansion of transformed plasma cells in the bone marrow and NK cells have a key role in the surveillance of this type of tumor. Increasing evidence denote that therapies designed to kill cancer cells and to simultaneously sustain host antitumor immunity are an appealing strategy to control tumor growth. NK cells can either sense damaged cells through the recognition of different activating ligands and at the same time they are able to detect Damage associated molecular patterns (DAMPs) released by abnormal cells through Toll-like receptors. In the cross-talk between NK and malignant cells, tumor cells release a wide range of soluble factors and extracellular vesicles, including exosomes, that could modulate NK cell-mediated functions. Recently, the importance of reciprocal exchange of exosomes from both stromal and MM cells has emerged as a pivotal mechanism facilitating tumor growth and progression suggesting a role of exosomes in the cross-talk between MM and stromal cells but little is known about effect of MM-cell derived exosomes on immune cells in the tumor microenvironment. The major objective of this proposal is to delineate how the multiple mieloma derived exosomes contribute to regulate the NK cell-mediated functions with particular attention given to the exosomal DAMPs (i.e: Hsp70 and HMGB1) able to interact with TLR2. We will study how chemotherapy can affect the exosome release and the amount of DAMPs associated to these nanovesicles and how this circumstance might affect their biological activity. These results point to improve either the efficacy of chemotherapy to boost the immune response and also to design new immunostimulatory nanoparticles to be used in combination with chemotherapy.
Several immunotherapies aimed at boosting immune response have recently been proposed and they include monoclonal antibodies, antibody¿drug conjugates, chimeric antigen receptor T cell therapy (CAR-T cells), tumor vaccines, and immune checkpoint inhibitors. Emerging studies have shown that therapies designed to kill cancer cells and to simultaneously sustain host antitumor immunity represent a promising strategy to control tumor growth. In regard to MM cancer model, accumulating evidence indicates that microenvironment transformation may significantly impair NK cell effector functions in MM (Pittari et al., Frontiers in Immunol, 2017). Thus, our project is aimed at potentiating the NK cell mediated functions against malignant MM cells. Exosomes represent important players of intercellular communications and recent studies have shown that these type of nanovesicles can carry DAMPs able to trigger innate immune cells (Yu-Ling et al., Cancer Sci, 2018). It is intriguing that different type of stress including anti-cancer agents can increase the exosome release, thus exosomes represent crucial targets to improve the efficacy of cancer immunothearapy. On the other hand, the production of synthetic nanoparticles mimicking exosome lipid composition (Caracciolo et al., Trends Biotechnol., 2017) and expressing immunomodulating molecules like DAMPs may represent another way to promote the NK cell battle against cancer. Our findings will provide new insights to understand: i) the importance of exosomes in cancer immunotherapy ii) their possible use as biomarkers and iii) the use of synthetic immunomodulatory nanoparticles-like exosomes in therapeutic protocols. We envisage that new strategies aimed at strengthening NK cells functions hold promise in MM and might be appealing to improve survival outcomes in patients.