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Background  Regulatory 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 Finding  We 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-DR high ) 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.    Conclusions  The 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.

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