IL-33 Released in the Liver Inhibits Tumor Growth via Promotion of CD4(+) and CD8(+) T Cell Responses in Hepatocellular Carcinoma

IL-33 released by epithelial cells and immune cells functions as an alarmin and can induce both type 1 and type 2 immune responses. However, the role of IL-33 release in tumor development is still not clear. In this study, we examined the function of released IL-33 in murine hepatocellular carcinoma (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 release. This antitumor effect of IL-33 was dependent on suppression of tumorigenicity 2 (ST2) because it was diminished in ST2(-/-) mice. Moreover, HCC patients with high IL-33 expression have prolonged overall survival compared with the patients with low IL-33 expression. Further study showed that there were increased percentages and numbers of activated and effector CD4(+) and CD8(+) T cells in both spleen and liver in IL-33-expressing tumor-bearing mice. Moreover, IFN-gamma production of the CD4(+) and CD8(+) T cells was upregulated in both spleen and liver by IL-33. The cytotoxicity of CTLs from IL-33-expressing mice was also enhanced. In vitro rIL-33 treatment could preferentially expand CD8(+) T cells and promote CD4(+) and CD8(+) T cell activation and IFN-gamma production. Depletion of CD4(+) and CD8(+) T cells diminished the antitumor activity of IL-33, suggesting that the antitumor function of released IL-33 was mediated by both CD4(+) and CD8(+) T cells. Taken together, we demonstrated in murine HCC models that IL-33 release could inhibit tumor development through its interaction with ST2 to promote antitumor CD4(+) and CD8(+) T cell responses.