Inflammasome- and gasdermin D-independent IL-1β production mobilizes neutrophils to inhibit antitumor immunity

Interleukin-1{beta} (IL-1{beta}) is a central mediator of inflammation whose secretion typically requires proteolytic maturation by the inflammasome and formation of membrane pores by gasdermin D (GSDMD). Emerging evidence suggests an important role for IL-1{beta} in promoting cancer progression in patients, but the underlying mechanisms are little understood. Here, we show a key role for IL-1{beta} in driving tumor progression in two distinct mouse tumor models. Notably, inflammasome activation and GSDMD were dispensable for the production of intratumoral bioactive IL-1{beta}, which promoted systemic mobilization and infiltration of neutrophils into tumors. Neutrophils recruited via IL-1{beta} suppressed the acquisition of an effector T-cell phenotype and subsequent antitumor immune response. Moreover, IL-1{beta} was essential for neutrophil accumulation upon antiangiogenic therapy, thereby contributing to therapy-induced immunosuppression. Antitumor immunity in the absence of IL-1{beta}-dependent neutrophil recruitment relied on immunostimulatory macrophages which promoted the infiltration and activation of cytotoxic T-cells. Overall, these results support a tumor-promoting role for IL-1{beta} through establishing an immunosuppressive microenvironment and show that inflammasome activation is not essential for its release in tumors.