IL-33 inhibits tumor growth through the activation of anti-tumor CD8+ T cell response in hepatocellular carcinoma

Abstract

Abstract IL-33 secreted by epithelial cells and activated innate immune cells is a member of IL-1 family with dual-immunological effects. It can induce both type 1 and type 2 immune responses and its function as an alarmin has been well demonstrated. However, the role of IL-33 in the development of hepatocellular carcinoma (HCC) is not clear. Here, we examined the function of IL-33 in various murine HCC models by hydrodynamically injecting either IL-33-expressing tumor cells or IL-33-expressing plasmids into the liver of tumor-bearing mice. Tumor growth was greatly inhibited by IL-33 expression. Similarly, in DEN-induced HCC model, we also demonstrated that IL-33 expression inhibited tumor development. This effect was shown to be dependent on extracellular IL-33 and ST2 expression, because it was diminished in ST2 KO mice. Further study showed there were increased percentages and numbers of CD8+ T cells in both spleen and liver in IL-33-expressing tumor-bearing mice. The percentages and numbers of activated and effector CD4+ and CD8+ T cells were also increased in the liver with IL-33 expression. Moreover, IFN-γ production of the CD8+ T cells was upregulated in both spleen and liver by IL-33. The cytotoxicity of CTLs against tumor cells was also enhanced. Depletion of CD8+ and CD4+T cells diminished the antitumor activity of IL-33, suggesting the anti-tumor function of IL-33 was T cell-dependent. In vitro IL-33 treatment could preferentially expand CD8+ T cells and promote their activation and IFN-γ production. Taken together, we demonstrated in murine HCC models that IL-33 could inhibit tumor development through its interaction with ST2 to promote anti-tumor CD8+ T cell response.