Increased liver-infiltrating CD8+FoxP3+ regulatory T cells are associated with tumor stage in hepatocellular carcinoma patients.

ABSTRACT

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver, and patients who are diagnosed with this tumor typically have a poor prognosis. The suppressive effects of CD4(+)FoxP3(+) regulatory T cells on antitumor immune response in HCC have been studied in great detail. CD8(+)FoxP3(+) regulatory T cells have recently been detected in tumors; however, the role of CD8(+)FoxP3(+) regulatory T cells in HCC is still unknown. Here, the frequency and phenotype of CD8(+)FoxP3(+) regulatory T cells were analyzed by multicolor flow cytometry in liver of HCC patients and healthy donors. We observed that the percentage of these cells in HCC patients was significantly higher than that observed in healthy control donors (p = 0.0155); their phenotype was close to that of CD4(+) regulatory T cells. Furthermore, we show that CD8(+)FoxP3(+) regulatory T cells are activated and act as effector memory cells (EM, CD45RA(-)CCR7(-)CD27(+/-)CD28(+)). Most importantly, a higher percentage of intrahepatic CD8(+)FoxP3(+) regulatory T cells was found in patients with advanced HCC than in those with early HCC in terms of tumor-node-metastasis (TNM) stage (stage I vs III, p = 0.0007). These data suggest that CD8(+)FoxP3(+) regulatory T cells may contribute to HCC immune escape and disease progression.