Possible contribution of circulating interleukin-10 (IL-10) to anti-tumor immunity and prognosis in patients with unresectable hepatocellular carcinoma

doi:10.1016/j.hepres.2003.07.002

Hepatology Research

Volume 27, Issue 4, December 2003, Pages 309-314

https://doi.org/10.1016/j.hepres.2003.07.002 Get rights and content

Abstract

Objectives: Interleukin-10 (IL-10) has been implicated in immune deficiency in patients with cancer. The relationship of this cytokine as measured in serum to anti-tumor immunity and prognosis was investigated in unresectable hepatocellular carcinoma. Methods: This study consisted of 74 consecutive patients with unresectable hepatocellular carcinoma (median age, 65 years). Forty-four healthy age-matched subjects and 32 patients with cirrhosis but no carcinoma served as controls. Patients with hepatocellular carcinoma were divided into those with serum IL-10 concentrations above (high group, n=39) or below (low group, n=35) 10 pg/ml. Results: Age, gender, Child–Pugh grade, and tumor stage distributions were similar in high and low groups. The patients of high group showed lower in lymphokine-activated killer (LAK) and natural killer (NK) activities than those of low group (P<0.01 and 0.01, respectively). Serum IL-10 concentration was a significant factor contributing to low activities of LAK and NK by logistic regression analysis (P<0.05 and 0.05, respectively). The high group had a significantly shorter survival (median, 3 months) than low group (median, 12 months; P<0.02, generalized Wilcoxon test). Conclusions: These data suggest that serum IL-10 concentration is a possible factor contributing to poor prognosis and low anti-tumor immunity in patients with unresectable hepatocellular carcinoma.

Introduction

Hepatocellular carcinoma (HCC) is a common malignancy that often occurs in patients with chronic liver disease, usually resulting from hepatitis B and C virus infection [1], [2]. Its incidence has substantially increased in Japan [3] and in western countries including the United States [4].

Cell-mediated cytotoxicity against tumor cells is an important component of immune surveillance against development and spread of malignant disease. Many reports have indicated lower natural killer (NK) and lymphokine-activated killer (LAK) activities of patients with solid tumors than in tumor-free subjects, and further impairment of these activities occurs in advanced stages of human cancer [5]. Although tumor-derived humoral factors with potent immunosuppressive activities have been proposed as causes of failure of cell-mediated cytotoxicity, a specific responsible factor remains to be identified in human cancers including HCC.

Interleukin-10 (IL-10) is a pleiotrophic cytokine produced by macrophages, T-helper 2 (Th2) cells and B-lymphocytes and can both stimulate and suppress the immune response [6]. IL-10 has been shown to inhibit various immune reactions, such as antigen presentation, cytokine production, macrophage activation, and antigen-specific T-cell proliferation. Recently, several lines of evidence proposed that IL-10 plays a key role in tumor development and metastasis [7], [8]. Increased circulating IL-10 has been reported in patients with different types of tumors including resectable HCC [9], [10], [11], [12]. Serum IL-10 concentration has been reported to be significantly elevated in patients with chronic hepatitis C and IL-10 may be related to hepatocarcinogenesis with suppression of immune surveillance [13]. However, little is known about the association between circulating IL-10 and anti-tumor immunity such as LAK and NK activities in HCC.

The present study was designed to investigate serum concentrations of IL-10 in patients with advanced HCC, to determine whether the cytokine is correlated with LAK and NK activities as well as outcome in the advanced disease.

Section snippets

Patients

Seventy-four consecutive patients (54 males, 20 females) with unresectable HCC were studied prospectively in Yamagata University Hospitals. The median age of the patients was 65 years (range: 41–88). Diagnosis of HCC was done with ultrasonography, computed tomography, and hepatic artery angiography. The diagnosis of HCC was confirmed histologically by examination of liver biopsy or autopsy specimens. At the time of study entry, 67 patients had a histological diagnosis of cirrhosis of the liver

Serum IL-10 concentrations of patients with HCC

Serum IL-10 concentrations of the patients with HCC (median 10.7 pg/ml, range: 2.0–61.2 pg/ml) were significantly higher than those of the patients with cirrhosis but no HCC (median 6.5 pg/ml, range: 3.7–20.5) and the healthy subjects (median 5.8 pg/ml; range: 4.0–14.0; P<0.001 and 0.01, respectively; Mann–Whitney test). Medians of the serum concentrations of patients with II, III and IV of tumor stage were 5.2 pg/ml (range: 2.0–12.5), 11.4 pg/ml (range: 2.5–24.3) and 12.6 pg/ml (range: 2.3–61.2),

Discussion

Elevated concentrations of circulating IL-10 have been observed in patients with chronic hepatitis, cirrhosis, and resectable HCC [12], [13], [21]. The concentrations are closely associated with disease progression. In addition, high levels of serum IL-10 are associated with a poor response to interferon treatment in patients with chronic hepatitis C [22], and polymorphisms of IL-10 gene are possible predictors of effectiveness with the treatment [23], [24].

IL-10 seems to be produced as

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Patients with HBV-related HCC who received HCC treatment (surgery or radiofrequency ablation [RFA]) and underwent long-term ETV or TDF therapy were retrospectively included. Baseline characteristics including age, sex, antiviral therapy, liver reserve, HCC stages, pathology reports and treatment modality were obtained. The risk of tumor recurrence, all-cause mortality, HCC-related mortality, and liver function were compared.
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This finding demonstrates that these changes occurred on a systemic level and proved the efficacy of the examined treatment by inhibiting the pro-inflammatory TNF-α with the stimulation of IL-10 production. In contrast to our finding, several studies reported a significant increase in the serum level of IL-10 during HCC pathogenesis (Zekri et al., 2005; Hattori et al., 2003; Hsia et al., 2007; El-Emshaty et al., 2015). This contrast could be referred to the route of administration of the xenobiotic used in the induction of HCC or the duration time of its administration period.
The present study investigates the efficacy of Terminalia muelleri ethanol extract (TME) in alleviating the oxidative stress and inflammation that could be the main player of hepatocellular carcinoma (HCC) development and progression. Forty-eight male albino rats were divided into two main groups (32 rats for DENA administration; 16 rats for control groups); after the induction period of DENA administration (6 weeks), the HCC-induced rats were treated with TME, DOX, or their combination for eight weeks. The obtained results revealed that the DENA induced HCC resulted in remarkable dysregulation in the circulatory levels of TNF-α and IL-10 that accompanied by the initiation of free radicals with the generation of the oxidative stress, in addition to an increase in the mRNA expression levels of NF_kB, MMP 9 and downregulation of mRNA expression level of TIMP1. The treatment of HCC induced rats with DOX, TME, or their combination alleviated and suppressed the progression of HCC in the following manner TME + DOX followed by TME then DOX. The obtained results revealed that TME was more valuable as an anti-cancer agent than DOX, employed in the current study as reference chemotherapy. T. muelleri extract attenuates inflammation, oxidative stress, and extracellular matrix proteolysis in hepatocellular carcinoma-induced rats.
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This poor prognostic signature includes an increase in immunosuppressive cytokines (IL-4, IL-5, IL-8, and IL-10) accompanied by suppression of immune activating cytokines (IL-1, tumor necrosis factor (TNF), and interferon gamma (IFN-γ)) [51]. Furthermore, increased IL-10 levels in patients with advanced HCC have been associated with shorter OS and immune dysfunction, such as diminished activity of lymphokine-activated killer (LAK) and natural killer (NK) cells [52]. On a receptor and ligand level, HCC immune tolerance is mediated by immunosuppression via decreased co-stimulatory or increased inhibitory checkpoint signaling.
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Possible contribution of circulating interleukin-10 (IL-10) to anti-tumor immunity and prognosis in patients with unresectable hepatocellular carcinoma

Abstract

Introduction

Section snippets

Patients

Serum IL-10 concentrations of patients with HCC

Discussion

Hepatocellular carcinoma: recent progress

Hepatology

Hepatitis c and hepatocellular carcinoma

Seminar Liver Dis.

Changing incidence of hepatocellular carcinoma in Japan

Cancer Res.

Rising incidence of hepatocellular carcinoma in the United States

New Engl. J. Med.

Human large granular lymphocytes and their relationship to natural killer cell activity in various diseases state

Blood

Biologic properties of interleukin-10

J. Clin. Immunol.

Interleukin-10 and cancer

Cancer Invest.

Interleukin-10 is a potent inhibitor of tumor cytotoxicity by human monocytes and alveolar macrophages

J. Leukocyte Biol.

Increased interleukin-10 serum levels in patients with solid tumors

Cancer Lett.

Serum interleukin-10 in early stage multiple myeloma

Lancet

Serum interleukin-10 in non-Hodgkin’s lymphoma: a prognostic factor

Blood

Serum interleukin-10 but not interleukin-6 is related to clinical outcome in patients with resectable hepatocellular carcinoma

Ann. Surg.

Serum levels of IL-10, IL-15 and soluble tumor necrosis factor-alpha (TNF-α) receptors in type C chronic liver disease

Clin. Exp. Immunol.

Transection of the oesophagus for bleeding oesophageal varices

Br. J. Surg.

Clinical and statistical validity of conventional prognostic factors in predicting short-term survival among cirrhosis

Hepatology

Interleukin-6 in transcatheter arterial embolization for patients with hepatocellular carcinoma

Cancer

Studies of human natural killer cells. II. Analysis at the single cell level

J. Immunol.