Interleukin-37 Promotes Colitis-associated Carcinogenesis (CAC) via SIGIRR-mediated Cytotoxic T Cells Exhaustion

Abstract Interleukin-37 (IL-37), a ligand of the IL-1 cytokine family, was identified as a fundamental inhibitor of innate immunity, having emerged as a dual-function cytokine with extracellular (ligation with receptor SIGIRR) and intra-(interaction with smad3) properties for regulating inflammatory response. However, the role and molecular mechanism of IL-37 in CAC has been rarely reported. IL-37 expression was highly expressed in human colorectal cancer tissues and predicted poor prognosis. Indeed, mice with transgenic expression of IL-37 (IL-37tg mice) were highly susceptible to colorectal cancer induced by AOM/DSS and suffered from dramatically increased tumor burdens in the colon. Nevertheless, aggravated epithelial disruption in IL-37tg mice was observed during DSS-induced injury, which was dependent on the presence of commensal bacteria through MAPK and mTOR pathways. Plus, IL-37 did not affect growth or enhance mutagenesis of transformed colonic epithelia cells. These results demonstrated that decreased proliferation of epithelia cells in response to DSS injury in CAC model is unlikely to be responsible for susceptibility in IL-37tg mice. Significant deficiency and dysfunction of cytotoxic T cells was consistently found in colonic lamina propria in IL-37 tg mice. This exhaustion led by IL-37 was dependent on checkpoint SIGIRR-mediated TIR signaling blocking, independent of TGF-β/smad3 signaling agonizing or antagonizing, and not caused by common immune-checkpoints. Our findings highlight a role for IL-37 in harnessing antitumor immunity by inactivation of cytotoxic T cells and establish new inhibitory checkpoint IL-37/SIGIRR in the cancer-immunity cycle as therapeutic targets in colorectal cancer.