Introduction
Liver cancer mainly includes hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma, hepatoblastoma, hepatocellular adenoma, and pediatric neoplasms according to the origin of liver tumorigenesis and molecular features [1]. HCC is the most common primary liver cancer and accounts for > 80% of liver tumors. HCC exacts a heavy disease burden and is the sixth most common cancer and the fourth leading cause of cancer-related deaths worldwide [2, 3].
The incidence of HCC and mortality rate have been increasing, with almost 800,000 newly diagnosed cases each year in recent decades.[1] The prognosis of HCC is poor with a 3-year survival rate of 12.7% and a median survival of 9 months. HCC can be treated with surgical resection, liver transplantation, liver-directed therapy, and systemic therapy [4]. Unfortunately, > 50% of systemic therapies available for HCC patients are minimally effective and might exert considerable toxic damage to the remaining normal liver, further limiting clinical outcomes [5]. Given the poor prognosis, attempts to explore new alternatives to HCC therapy are necessary.
The liver microenvironment contains a large population of lymphocytes with strong anti-tumor function, including T cells, natural killer cells, natural killer T cells, mucosal-associated invariant T cells, and gamma delta T cells [6]. Most HCCs are a consequence of chronic infection with hepatitis B virus and hepatitis C virus or different metabolic and inflammatory disorders related to non-alcoholic steatohepatitis and alcoholic steatohepatitis (5). Long-term hepatic inflammatory responses, characterized by continued cytokine expression and immune cell infiltration, might lead to the changes in the liver immunologic microenvironment, which are essential risk factors for hepatocarcinogenesis [7]. The decrease in cytotoxic function and increase in the frequency of Tregs and release of suppressive cytokines lead to HCC tolerance and growth.
Interleukin (IL)-35 is the newest member of the IL-12 family and is predominantly produced by Tregs (8). As an anti-inflammatory and immune inhibitory cytokine, IL-35 has been shown to have potent immunosuppressive effects in immune evasion [8]. Research focusing on the presence or geographic location of IL-35 has uncovered a much larger tissue distribution. Subunits of IL-35, EBI3, and IL-12 p35 have been detected in placental trophoblasts, Hodgkin lymphoma cells, acute myeloid leukemia cells, lung cancer cells, esophageal carcinoma, HCC, pancreatic ductal adenocarcinoma, cervical carcinoma, and colorectal cancer [9]. Detection in HCC patients indicated that high liver IL-35 expression correlates with tumor aggressiveness and post-operative recurrence [10]. Similar research in intrahepatic cholangiocarcinoma patients showed that a high IL-35 level is positively associated with aggressiveness and can serve as a prognostic factor [11]. In contrast, Long et al. (13) revealed decreased expression of IL-35 in HCC patients with increasing AJCC TNM stage, worse histologic grade, larger tumor size, and histologic identification with micro-vascular invasion and lymph node/distant metastasis. Therefore, more studies are needed to concentrate on the relationship between immune status and the level of IL-35 expression. In this study, we determined the expression of IL-35 in serum and tumor samples from HCC patients. Furthermore, our results proposed that IL-35 might play essential roles in tumor growth by inhibiting T cell cytotoxicity and T cell exhaustion.