Systemic application of IL-33 for cancer immunoprevention and immunotherapy

The local cell-extrinsic and cell-intrinsic roles of endogenous interleukin-33 (IL-33) in tumor progression and metastasis have been controversial, which has delayed scrutiny of the systemic application of IL-33 in tumor immunoprevention and immunotherapy. A prominent concern regards 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 in suppressor of tumorigenicity 2⁺ (ST2⁺) T_reg cells. Unexpectedly, systemic IL-33 treatment constrains tumor growth in a T_reg ST2-dependent manner, although the endogenous IL-33/ST2 axis in T_reg cells promotes tumor growth. Indeed, IL-33 reprograms T_reg cells toward a cytotoxic and inflammatory phenotype. Lastly, we fail to show that 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.