Inflammasome activation in macrophages limits CD8+ T cell response to radiotherapy 2430

Abstract Description Radiation therapy (RT) induces immunogenic cell death by releasing tumor antigens and endogenous adjuvants that activate the immune system. MyD88 signaling in myeloid cells restricts CD8+ T cell responses to RT in pancreatic cancer and we hypothesized that inflammasome activation occurs downstream of MyD88 post-RT. We observed increased levels of IL-1B and increased ASC-mCitrinebright monocytes and macrophages 24h post-RT, indicative of inflammasome activation. We identified P2X7R, glutathione, and mitochondrial ROS as critical mediators of inflammasome activation in macrophages responding to dying cancer cells post-RT. Caspase 1 inhibition significantly improved survival post-RT dependent on CD8+ T cells in male mice. Estrogen and progesterone inhibited inflammasome activation in co-cultures in vitro, while tamoxifen and mifepristone were required to restore the survival benefits of caspase-1 inhibition and RT in females. In males, Caspase-1 blockade led to a reduction in CD8+ T cell heterogeneity in the tumor draining LN, favoring expansion of a dominant activated effector phenotype marked by elevated expression of T-bet, Eomes, and Ki67. The functional implications of these findings were underscored by the increased antigen-specific CD8+ T cells intratumorally. These findings demonstrate that inflammasome activation in macrophages is a sex-dependent response that suppresses the immune response to RT and its blockade improves outcomes dependent on CD8+ T cells. Funding Sources Collins Medical Trust K22 CA251643 Providence Foundation Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)