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.