Inflammation-dependent IL-18 signaling restricts hepatocellular carcinoma growth by enhancing the accumulation and activity of tumor-infiltrating lymphocytes

Chronic inflammation in liver tissue is an underlying cause of hepatocellular carcinoma (HCC). High levels of inflammatory cytokine interleukin IL-18 in the circulation of patients with HCC correlates with poor prognosis. However, conflicting results have been reported for IL-18 in HCC development and progression. In this study, we used tissue specimens from HCC patients and clinically relevant mouse models of HCC to evaluate IL-18 expression and function. In a mouse model of liver fibrosis that recapitulates a tumor-promoting microenvironment, global deletion of the IL-18 receptor IL18R1 enhanced tumor growth and burden. Similarly, in a carcinogen-induced model of liver tumorigenesis, IL18R1 deletion increased tumor burden. Mechanistically, we found that IL-18 exerted inflammation-dependent tumor-suppressive effects largely by promoting the differentiation, activity and survival of tumor-infiltrating T cells. Finally, differences in the expression of IL-18 in tumor tissue versus non-tumor tissue was more predictive of patient outcome than overall tissue expression. Taken together, our findings resolve a long-standing contradiction regarding a tumor-suppressive role for IL-18 in established HCC and provide a mechanistic explanation for the complex relationship between its expression pattern and HCC prognosis.

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