IL1b promotes immune suppression in the tumor microenvironment independent of the inflammasome and gasdermin D

Abstract

IL1b is a central mediator of inflammation. Secretion of IL1b typically requires proteolytic maturation by the inflammasome and formation of membrane pores by gasdermin D (GSDMD). Emerging evidence suggests an important role for IL1b in promoting cancer progression in patients, but the underlying mechanisms are ill-defined. Here, we have shown a key role for IL1b in driving tumor progression in two distinct mouse tumor models. Notably, activation of the inflammasome, caspase-8, as well as the pore-forming proteins GSDMD and mixed lineage kinase domain–like protein in the host were dispensable for the release of intratumoral bioactive IL1b. Inflammasome-independent IL1b release promoted systemic neutrophil expansion and fostered accumulation of T-cell–suppressive neutrophils in the tumor. Moreover, IL1b was essential for neutrophil infiltration triggered by antiangiogenic therapy, thereby contributing to treatment-induced immunosuppression. Deletion of IL1b allowed intratumoral accumulation of CD8þ effector T cells that subsequently activated tumor-associated macrophages. Depletion of either CD8þ T cells or macrophages abolished tumor growth inhibition in IL1b-deficient mice, demonstrating a crucial role for CD8þ T-cell–macrophage cross-talk in the antitumor immune response. Overall, these results support a tumor-promoting role for IL1b through establishing an immunosuppressive microenvironment and show that inflammasome activation is not essential for release of this cytokine in tumors.