Regulatory T cells, especially ICOS+ FOXP3+ regulatory T cells, are increased in the hepatocellular carcinoma microenvironment and predict reduced survival.

Jian-Fei Tu,Xin-Mu Zhou,Xi-Hui Ying,Deng-Ke Zhang,Ya-Hui Ding,Jian-Song Ji,Hai Zou,Fa-Zong Wu

doi:10.1038/srep35056

Abstract

Hepatocellular carcinoma (HCC) is a common malignant tumour, especially in Asia. Its prognosis is poor, and there are limited methods for predicting patient survival. This study was carried out to analyse the prognostic value of tumour-infiltrating lymphocytes (TILs), especially regulatory T cells (Tregs), in HCC patients. TILs were analysed in 57 randomly selected HCC patients. The prognostic effects of groups with high and low numbers were evaluated by the Kaplan-Meier and Cox model analyses. Although higher densities of CD3+, CD4+, and CD8+ cytotoxic lymphocytes (CTLs) as well as CD56+ NK cells and CD68+ macrophages were observed in peritumoural tissue, increased numbers of forkhead/winged helix transcription factor P3+ (FOXP3+) Tregs were found in intratumoural tissue. Additionally, regarding ICOS+ FOXP3+ Tregs, an increased prevalence in carcinoma was not only associated with the absolute number but also with the percentage of FOXP3+ cells. Higher Treg levels in tumour tissues indicated a worse prognosis, and the FOXP3+ Tregs/CD4+ T cells ratio was an independent prognostic factor for OS. Therefore, FOXP3+ Tregs, especially ICOS+ FOXP3+ Tregs, contribute to the immunosuppressive HCC microenvironment. High tumour-infiltrating Tregs are thought to be an unfavourable prognostic indicator of HCC.

Highlights

Secretion of immune-suppressive cytokines[9,10]
In the present study, increased Tregs in Hepatocellular carcinoma (HCC) carcinoma tissues were found, which was consistent with previous reports[23]
FOXP3+ Tregs can be divided into two subsets, inducible costimulator (ICOS)+ and ICOS− Tregs, according to their ICOS expression

Summary

Introduction

Secretion of immune-suppressive cytokines[9,10]. There is accumulating evidence that an increased population of Tregs in TILs or peripheral blood mononuclear cells (PBMCs) is one of the reasons for impaired anti-tumour immunity in cancer-bearing hosts[11,12]. Studies have demonstrated that the proportion of Tregs is increased in TILs and peripheral blood from patients with pancreas/breast adenocarcinoma as well as prostate, ovarian and lung cancers[13,14,15] These cells prevent activated CD4+ CD25− and CD8+ cells from proliferating, which mitigate the immune response against tumour antigens[13] and associate with tumour prognoses[12,16]. After patients receive curative resections for gastric cancer, the increased proportion of Tregs is significantly reduced, and the levels are almost equal to those in normal healthy donors[17]. These results strongly suggest that tumour-related factors induce and expand Tregs. We will focus on ICOS expression on Treg surfaces and analyse the possible mechanisms of Treg recruitment

Methods

Results

Conclusion