| dc.description.abstract | The inflammasome is a multi-protein signaling pathway in immune and epithelial cells important for activation of the innate immune system and protection from pathogens. We previously showed that caspase-1 signaling in myeloid derived suppressor cells (MDSCs) promotes T cell independent cancer progression, but an in depth understanding of inflammasome signaling in the highly heterogeneous myeloid cells in the tumor milieu remains elusive. Further, the direct effects of inflammasome signaling on T cell anti-tumor responses are unknown. To help resolve this complexity, single cell transcriptomic profiles of human head & neck squamous cell carcinoma (HNSCC) identified distinct inflammasome gene set transcriptomic activity within specific clusters of tumor-infiltrating myeloid cells, and NLRP3 sensor and downstream effector IL-1β transcripts were increased in multiple monocytic and macrophage subtypes in the tumor microenvironment (TME). In vivo, we showed that the NLRP3 phenocopied caspase-1/IL-1β dependent tumor progression. We found that myeloid-intrinsic caspase-1 signaling within the TME increased tumor infiltrating myeloid survival. We identified that macrophage mediated efferocytosis of dying tumor cells in the TME directly activates NLRP3 dependent inflammasome signaling to drive IL-1β secretion and promote tumor growth. In addition, we show the importance of inflammasome expression and activation in tumor infiltrating T cells. We find that caspase-1 null T cells are phenotypically altered resulting in increased cytotoxicity both in vitro and in vivo. Further, checkpoint molecule expression is elevated PD-1 expression in caspase-1 KO T cells; thus, combination caspase-1 and PD-1 blockade results in a significant reduction in tumor burden. We propose that T cell-intrinsic inflammasome signaling acts as a negative regulator to inhibit T cell activation and cytotoxicity. Cumulatively, we provide a novel inflammasome signaling axis between tumor and myeloid cells that characterizes chronic inflammation induced malignancy. Further, we identify a novel targetable T cell-intrinsic checkpoint mechanism. | |
