Prognostic value of tumor-infiltrating FOXP3+ regulatory T cells in patients with hepatocellular carcinoma.

CD4+ CD25+ forkhead box P3 (FOXP3)+ T(reg) accumulate in malignant tumors and negatively regulate anti-tumor immunity. To determine the prognostic value of tumor-infiltrating regulatory T cells (T(reg)), we conducted a retrospective study on 164 patients with hepatocellular carcinoma (HCC) who underwent curative hepatic resection. We investigated the number of tumor-infiltrating FOXP3+ T(reg) in formalin-fixed HCC specimens. The number of FOXP3+ T(reg) for each case was calculated as the total number of positive cells per 10 high-power fields (HPF) on light microscopy. Long-term survival rate after resection according to the number of FOXP3+ T(reg) was accessed by univariate and multivariate analyses. The mean and median numbers of tumor-infiltrating T(reg) were 29.0 and 14 per 10 HPF for FOXP3+ T(reg). The number of FOXP3+ T(reg) was positively correlated with preoperative serum alpha-fetoprotein levels. The disease-free survival rate was significantly lower in patients with high T(reg) counts (> or =14, n=84) than in those with low T(reg) counts (<14, n=80) (13.6% vs. 25.7% at 5 years; P=0.02). By multivariate analysis, the high T(reg) counts, presence of portal vein invasion, and elevation of preoperative aspartate aminotransferase level were independent predictive factors of tumor recurrence. The high number of tumor-infiltrating T(reg) is an independent predictive factor of tumor recurrence after hepatic resection for HCC.