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

Eur J Surg Oncol. 2008 Feb;34(2):173-9. doi: 10.1016/j.ejso.2007.08.008. Epub 2007 Oct 10.


Aims: 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.

Methods: 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.

Results: 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.

Conclusions: The high number of tumor-infiltrating T(reg) is an independent predictive factor of tumor recurrence after hepatic resection for HCC.

MeSH terms

  • Adult
  • Aged
  • Biomarkers, Tumor / analysis*
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / mortality
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / surgery
  • Cohort Studies
  • Confidence Intervals
  • Disease-Free Survival
  • Female
  • Hepatectomy / methods
  • Hepatocyte Nuclear Factor 3-gamma / genetics
  • Hepatocyte Nuclear Factor 3-gamma / metabolism*
  • Humans
  • Immunohistochemistry
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / mortality
  • Liver Neoplasms / pathology
  • Liver Neoplasms / surgery
  • Lymphocytes, Tumor-Infiltrating / metabolism*
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Probability
  • Prognosis
  • Retrospective Studies
  • Risk Assessment
  • Sensitivity and Specificity
  • Survival Analysis
  • T-Lymphocytes, Regulatory / metabolism*


  • Biomarkers, Tumor
  • Hepatocyte Nuclear Factor 3-gamma