Abstract

The local cell-extrinsic and intrinsic roles of endogenous IL-33 in tumor progression and metastasis have been controversial, which has lagged the scrutinization on the systemic application of IL-33 in tumor immunoprevention and immunotherapy. A prominent concern is on its capacity in stabilizing the immunosuppressive phenotype of regulatory T (T reg ) cells. Here, we report that systemic IL-33 treatment potently promotes the effects of prophylactic tumor vaccines and inhibits the progression of mouse solid tumors. Mechanistically, systemic IL-33 treatment reshapes the tumor immune microenvironment, including the increase of ST2 + T reg cells. Unexpectedly, systemic IL-33 treatment constrains tumor growth in a T reg ST2-dependent manner, though endogenous IL-33/ST2 axis in T reg cells promotes tumor growth. Indeed, splenic CD4 + Foxp3 + cells from IL-33-treated mice reprograms T reg cells towards a cytotoxic and inflammatory phenotype. Lastly, we fail to show endogenous IL-33 promotes tumor growth. Thus, our findings elucidate a T reg ST2-dependent mechanism of the anti-tumor effect of systemic IL-33 application and support the use of IL-33 for cancer immunoprevention and immunotherapy.