Tumor RIPK1 signaling mediates intrinsic and extrinsic mechanisms of resistance to immune checkpoint blockade therapy

Abstract

Abstract Immune checkpoint blockade (ICB) therapy can result in impressive clinical responses of multiple cancer types, however resistance is common. Mechanisms of resistance include both tumor intrinsic evasion of immune mediated killing and tumor extrinsic features in the immune-microenvironment, such as poor infiltration of tumor reactive T cells and accumulation of immunosuppressive cells. By examining transcriptomic features associated with response or resistance to ICB, we found the expression of Receptor Interacting Protein Kinase 1 (RIPK1), a critical regulator of inflammation and cell death, is significantly higher in ICB resistant murine tumor cells. We hypothesized that RIPK1 expression in the tumor cells may influence both intrinsic and extrinsic mechanisms regulating response to ICB. To test this hypothesis, we genetically deleted RIPK1 in murine tumor cell lines and found improved overall survival upon treatment compared to tumors expressing RIPK1. Mechanistically, deletion of RIPK1 in the tumor cells results in favorable changes in the tumor microenvironment, including an increased frequency of effector T cells, a decreased frequency of immunosuppressive myeloid cells, and changes in inflammatory cytokine secretion that can impact these changes in immune infiltrate. Further, deletion of the apoptosis effector Caspase 8 reversed RIPK1 KO tumor sensitization to ICB, suggesting that tumor sensitization to cell death also contributes to improved response to ICB upon RIPK1 deletion. In conclusion, RIPK1 is an important regulator at the intersection of tumor intrinsic and extrinsic pathways governing response to ICB, and therefore is a potential target for combinatorial therapies to improve patient response to ICB.