Interleukin‐1 receptor 1 deficiency worsens hepatocellular carcinoma, while gemcitabine treatment alleviates the hepatocellular carcinoma‐induced increase in intra‐hepatic immune cells

Abstract

AbstractBackground and AimPrimary liver cancer, particularly hepatocellular carcinoma (HCC), represents a substantial global health challenge. Although immune checkpoint inhibitors are effective in HCC treatment, several patients still experience disease progression. Interleukin‐1 (IL‐1) regulates immunity and inflammation. We investigate the role of IL‐1 in HCC development and progression and determine the potential therapeutic impact of gemcitabine in treating HCC.MethodsHydrodynamics‐based transfection, employing the sleeping beauty transposase system, delivered surrogate tumor antigens, NRAS (NRAS proto‐oncogene, GTPase), ShP53, and SB100 to C57BL/6 mice. A basic HCC mouse model was established. Pathogen‐free animals were tested for serum and hepatotoxicity. The HCC prognosis was monitored using alanine aminotransferase and aspartate aminotransferase levels. Liver histology immunohistochemistry and mouse splenocyte/intra‐hepatic immune cell flow cytometry were conducted. IL‐1β levels in human and mouse serum were assessed.ResultsInterleukin‐1β levels were elevated in patients with HCC compared with those in non‐HCC controls. Hepatic IL‐1β levels were higher in HCC mouse models than those in non‐HCC mice, suggesting localized hepatic inflammation. IL‐1 receptor type 1 (IL‐1R1) knockout (IL‐1R1−/−) mice exhibited less severe HCC progression than that in wild‐type mice, despite the high intra‐hepatic IL‐1β concentration. IL‐1R1−/− mice exhibited increased hepatic levels of myeloid‐derived suppressor cells and regulatory T cells, which may exacerbate HCC. Gemcitabine significantly reduced the HCC tumor burden, improved liver conditions, and increased survival rates in HCC mouse models. Gemcitabine reduced the hepatic levels of myeloid‐derived suppressor cells and regulatory T cells, potentially alleviating immune suppression in the liver.ConclusionsTargeting IL‐1 or combining gemcitabine with immunotherapy is a promising approach for treating advanced‐stage HCC.