IL1β Promotes Immune Suppression in the Tumor Microenvironment Independent of the Inflammasome and Gasdermin D

IL1 beta is a central mediator of inflammation. Secretion of IL1 beta typically requires proteolytic maturation by the inflammasome and formation of membrane pores by gasdermin D (GSDMD). Emerging evidence suggests an important role for IL1 beta in promoting cancer progression in patients, but the underlying mechanisms are ill-defined. Here, we have shown a key role for IL1 beta 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 IL1 beta. Inflammasome-independent IL1 beta release promoted systemic neutrophil expansion and fostered accumulation of T-cell-suppressive neutrophils in the tumor. Moreover, IL1 beta was essential for neutrophil infiltration triggered by antiangiogenic therapy, thereby contributing to treatment-induced immunosuppression. Deletion of IL1 beta allowed intratumoral accumulation of CD8(+) effectorT cells that subsequently activated tumor-associated macrophages. Depletion of either CD8(+) T cells or macrophages abolished tumor growth inhibition in IL1 beta-deficient mice, demonstrating a crucial role for CD8(+) T-cell-macrophage cross-talk in the antitumor immune response. Overall, these results support a tumor-romoting role for IL1 beta through establishing an immunosuppressive microenvironment and show that inflammasome activation is not essential for release of this cytokine in tumors.

Automated summary

IL-1β plays a crucial role in promoting tumor progression and establishing an immunosuppressive microenvironment. The release of IL-1β may not necessarily require inflammasome activation. The crosstalk between CD8(+) T cells and macrophages is essential for anti-tumor immune response.