Selective Recruitment of Regulatory T Cell through CCR6-CCL20 in Hepatocellular Carcinoma Fosters Tumor Progression and Predicts Poor Prognosis

Abstract

BackgroundRegulatory T cells (Tregs) are highly prevalent in tumor tissue and can suppress effective anti-tumor immune responses. However, the source of the increased tumor-infiltrating Tregs and their contribution to cancer progression remain poorly understood.Methodology/Principal FindingWe here investigated the frequency, phenotype and trafficking property of Tregs and their prognostic value in patients with hepatocellular carcinoma (HCC). Our results showed that FoxP3+ Tregs highly aggregated and were in an activated phenotype (CD69+HLA-DRhigh) in the tumor site, where they can suppress the proliferation and INF-γ secretion of CD4+CD25− T cells. These tumor-infiltrating Tregs could be selectively recruited though CCR6-CCL20 axis as illustrated by (a) high expression of CCR6 on circulating Tregs and their selective migration to CCR6 ligand CCL20, and (b) correlation of distribution and expression between tumor-infiltrating Tregs and intratumoral CCL20. In addition, we found that the number of tumor-infiltrating Tregs was associated with cirrhosis background (P = 0.011) and tumor differentiation (P = 0.003), and was an independent prognostic factor for overall survival (HR = 2.408, P = 0.013) and disease-free survival (HR = 2.204, P = 0.041). The increased tumor-infiltrating Tregs predicted poorer prognosis in HCC patients.ConclusionsThe CCL20-CCR6 axis mediates the migration of circulating Tregs into tumor microenvironment, which in turn results in tumor progression and poor prognosis in HCC patients. Thus, blocking CCL20-CCR6 axis-mediated Treg migration may be a novel therapeutic target for HCC.

Prediction of Recurrence and Survival in Hepatocellular Carcinoma Based on Two Cox Models Mainly Determined by FoxP3+ Regulatory T Cells

“…Chemokines are critical for attracting immune cells (27). Our previous data have shown that CCL20 mediates the migration of Tregs into tumor microenvironment (18). Here, we further found the expression of CXCL16 correlated with the number of FoxP3 þ cells (P ¼ 0.005; r ¼ 0.668; Fig.…”

Hypoxia-Induced Epithelial-to-Mesenchymal Transition in Hepatocellular Carcinoma Induces an Immunosuppressive Tumor Microenvironment to Promote Metastasis

“…Previous studies showed that the CCL20-CCR6 axis is important for the recruitment of circulating T regs into the tumor microenvironment (43). Here, we demonstrated that CCL20-treated IDO þ monocyte-derived macrophages significantly inhibited the T-cell proliferative activity compared with untreated monocytederived macrophages in an IDO-dependent way.…”

Prognostic significance of regulatory T lymphocytes in patients with hepatocellular carcinoma

“…Our search strategy yielded 573 primary articles, of which 16 were eventually identified fulfilling the eligibility criteria (Fu et al, 2007;Gao et al, 2007;Kobayashi et al, 2007;Sasaki et al, 2008;Cai et al, 2009;Ju et al, 2009a;2009b;Zhou et al, 2009;2010;Chen et al, 2011;Shen et al, 2011;Huang et al, 2012;Mathai et al, 2012;Wang et al, 2012;Lin et al, 2013) (Fig. 1).…”