Endogenous IL-33 exerts CD8⁺ T cell antitumor responses overcoming pro-tumor effects by regulatory T cells in a colon carcinoma model

Interleukin-33 (IL-33) is a nuclear-associated cytokine of the IL-1 family. IL-33 and its receptor ST2 axis exert conflicting anti-tumor and pro-tumor effects in various tumors. In this study, we examined the role of endogenously produced IL-33 in the colon-26 tumor model, in which involvement of the IL-33:ST2 pathway was negligible on the tumor side. We found that the generation of regulatory T cells (Tregs) and CD8⁺ T cells, and IFN-γ expression by both CD4⁺ and CD8⁺ T cells (T cell activation) were impaired in IL-33-deficient mice. Overall antitumor responses, assessed by tumor growth and IFN-γ expression by tumor-infiltrating CD8⁺ T cells, were also impaired, even after Treg adjustment prior to tumor inoculation. These results indicate that endogenous IL-33 augmented CD8⁺ T cell-mediated antitumor responses in this colon carcinoma model, with higher CD8⁺ T cell-infiltration and overcoming pro-tumor effects by increased Tregs. Exogenous application of IL-33 into the tumors did not enhance CD8⁺ T cell-mediated antitumor responses despite marked elevation of innate responses showing upregulation of proinflammatory cytokine/chemokine expression, neutrophil recruitment, and dendritic cell activation. Our results suggest a dual role for endogenous IL-33 in antitumor responses and suggest that the balance of CD8⁺ T cells:Tregs in the tumor microenvironment is one of key factors for estimating the contribution of IL-33-mediated antitumor responses. Therefore, the development of IL-33-based cancer immunotherapy may require a target cell-specific approach.