Inflammation-Dependent IL18 Signaling Restricts Hepatocellular Carcinoma Growth by Enhancing the Accumulation and Activity of Tumor-Infiltrating Lymphocytes

Abstract

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.

Deficient Natural Killer Cell NKp30‐Mediated Function and Altered NCR3 Splice Variants in Hepatocellular Carcinoma

“…This difference in tissue‐specific NKp30 isoform profile and NK cell functionality prompted us to examine changes in the cytokine content in the neoplastic and the surrounding non‐neoplastic liver tissue. To this end, we analyzed mRNAs of selected cytokines that were previously shown to be involved in the necroinflammatory process leading to advanced fibrosis and liver carcinogenesis as well as in NK cell regulation . There was a reduced mRNA content of certain cytokines, including IL‐6, IL‐8 and IL‐10, in the tumor compared with the non‐neoplastic tissue, whereas no statistically significant differences were observed for IL‐18 and transforming growth factor (TGF)‐β mRNAs (Fig.…”

Downregulation of HuR Inhibits the Progression of Esophageal Cancer through Interleukin-18

“…It is reported that high levels of the inflammatory cytokine IL-18 in the circulation of patients with hepatocellular carcinoma correlated with poor prognosis. IL-18 exerted inflammation-dependent tumor-suppressive effects largely by promoting differentiation, activity and survival of tumor-infiltrating T cells [ 28 ]. In glioma cells, the involvement of HuR in the regulation of IL-18 has also been reported, which is consistent with our finding in ESCC cells.…”

Expression of Allograft Inflammatory Factor-1 (AIF-1) in Hepatocellular Carcinoma

“…In HCC, tumor burden has been shown to be an important prognostic marker [ 33 ]. Maximal tumor size and number of tumor nodules are related to overall survival of patients with HCC [ 34 ].…”