Inflammasome Signaling Mediates Myeloid Immunosuppression within the Tumor Microenvironment

Abstract

Abstract Myeloid Derived Suppressor Cells (MDSCs) are important mediators of immune evasion in cancer and have been associated with worse overall survival and progression free survival in patients with multiple types of solid tumors. While MDSCs were initially characterized to inhibit T cells and NK cells through the upregulation of iNOS and arginase-1 and production of Nitric Oxide, reactive oxygen species, TGF-β, and IL-10, there is now growing literature that MDSCs can promote cancer progression through other mechanisms. Here we propose that myeloid-intrinsic inflammasome activation plays a direct role in tumor progression. To investigate this, in vitro tumor proliferation studies were performed and show that CD11b+, Ly6C+ monocytic MDSCs isolated from tumor bearing mice promote inflammasome-dependent proliferation of multiple murine tumor cell lines. Mass cytometry and RNA sequencing data of human Head & Neck Squamous Cell Carcinoma patient samples indicate that the total myeloid immune infiltrate can differ greatly among patients. In cases where the T cell immune infiltrate is low, we propose that the infiltrating myeloid cells are utilizing inflammasome signaling to promote tumor progression. These results provide a greater understanding of the role of inflammasome signaling in MDSC-mediated immunosuppression within the tumor microenvironment which will allow for a better understanding of the function of MDSCs in cancer and identification of potential targetable components of MDSC signaling for cancer therapeutics.