Foxp3+ regulatory T cells are associated with the natural history of chronic hepatitis B and poor prognosis of hepatocellular carcinoma

Liver Int. 2012 Apr;32(4):644-55. doi: 10.1111/j.1478-3231.2011.02675.x. Epub 2011 Nov 28.


Background: Recent studies have focused on regulatory T cells (Tregs) in chronic hepatitis B (CHB) and hepatocellular carcinoma (HCC) and they were also conducted independently of each other.

Aims: This study tried to characterize Tregs in blood and tumour infiltration, and to explore the correlations between Tregs and the context of chronic hepatitis B in HCC patients.

Methods: The liver-resident Tregs and CD8(+) T cells on core biopsy were investigated using immunohistochemistry staining in individuals (n = 209) with CHB (n = 47), HCC (n = 137) or healthy controls (n = 25). Circulating Tregs were detected in the above patients with CHB (n = 27) or HCC (n = 101) by flow cytometry.

Results: The number of tumour-infiltrating and circulating FoxP3(+) Tregs was significantly high in patients with CHB (P < 0.001). However, there were fewer intratumoural Tregs in patients with advanced HCC than those in patients with early stage HCC (P = 0.043); In contrast, the circulating Tregs frequency increased during the progression of HCC (P = 0.024). Increased tumour-infiltrating and circulating FoxP3(+) Tregs were associated with poor overall survival (P = 0.041, 0.002 respectively) and a shorter time to recurrence (P = 0.049, 0.002 respectively) in patients with early stage HCC. Tumour-infiltrating Foxp3 + Tregs were related to chronic hepatitis B natural history in HCC (P = 0.012). Neither tumour-infiltrating CD8(+) T cells nor balance of intratumoural Tregs and CD8(+) T cells correlated with prognosis of HCC.

Conclusions: Increased Foxp3(+) Tregs may represent a prognostic predictor in patients with early stage HCC. The CHB natural history influenced density of tumour-infiltrating Tregs in hepatocellular carcinoma patients with chronic hepatitis B viruses infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Biomarkers, Tumor / immunology*
  • Carcinoma, Hepatocellular / immunology*
  • Case-Control Studies
  • China
  • Female
  • Flow Cytometry
  • Forkhead Transcription Factors / metabolism
  • Hepatitis B, Chronic / immunology*
  • Humans
  • Immunohistochemistry
  • Liver Neoplasms / immunology*
  • Male
  • Middle Aged
  • Prognosis
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism


  • Biomarkers, Tumor
  • FOXP3 protein, human
  • Forkhead Transcription Factors