Hepatocellular carcinoma (HCC) is the fifth most common cancer and third leading cause of cancer-related mortality world-wide. This cancer almost always develops upon the background of chronic pathological inflammation and resultant fibrosis, which regulate both the development and progression of this cancer. Interleukin 18 (IL-18), a member of the IL-1 family of cytokines, has been reported to be elevated in serum of patients with liver disease and HCC, however, its mechanistic significance remains poorly understood.

To explore this question, we evaluated patient serum and tissue samples, and found that while IL-18 was indeed elevated in comparison to healthy individuals, and its elevation correlated to worse survival of patients, its levels were decreased inside tumor compared to non-tumor tissue from the same patient. Utilizing an immune-competent mouse model with orthotopic tumor implantation into a fibrotic liver, we found that both knocking down IL-18 expression in mouse HCC cells implanted into wild-type mice and inoculating mouse HCC cells in an IL-18 receptor-deficient mouse resulted in enhanced tumor growth. Post-implantation, CD8+ T-cells were reduced and CD4+ T-cells mildly increased in tumors in the IL-18 receptor-deficient mice compared to wild-type controls, with a resultant robust change in CD8:CD4 T-cell ratio, while other IL-18-responsive cell types, such as NK cells, were unchanged. A chemically-induced carcinogenesis model also displayed increased tumor burden in IL-18 receptor-deficient mice compared to wild-type controls. Re-examination of patient samples revealed that magnitude of the difference in IL-18 expression between tumor and non-tumor liver correlated with patient prognosis, with worse prognosis in patients with less IL-18 inside the tumor compared with non-tumor liver tissues. These results suggest a possible biphasic role for IL-18 in the pathological process of this disease, and demonstrate a complex role for IL-18 in HCC tumorigenesis and progression.