Regulatory T cells, especially ICOS + FOXP3 + regulatory T cells, are increased in the hepatocellular carcinoma microenvironment and predict reduced survival

Sci Rep. 2016 Oct 11;6:35056. doi: 10.1038/srep35056.


Hepatocellular carcinoma (HCC) is a common malignant tumour, especially in Asia. Its prognosis is poor, and there are limited methods for predicting patient survival. This study was carried out to analyse the prognostic value of tumour-infiltrating lymphocytes (TILs), especially regulatory T cells (Tregs), in HCC patients. TILs were analysed in 57 randomly selected HCC patients. The prognostic effects of groups with high and low numbers were evaluated by the Kaplan-Meier and Cox model analyses. Although higher densities of CD3+, CD4+, and CD8+ cytotoxic lymphocytes (CTLs) as well as CD56+ NK cells and CD68+ macrophages were observed in peritumoural tissue, increased numbers of forkhead/winged helix transcription factor P3+ (FOXP3+) Tregs were found in intratumoural tissue. Additionally, regarding ICOS+ FOXP3+ Tregs, an increased prevalence in carcinoma was not only associated with the absolute number but also with the percentage of FOXP3+ cells. Higher Treg levels in tumour tissues indicated a worse prognosis, and the FOXP3+ Tregs/CD4+ T cells ratio was an independent prognostic factor for OS. Therefore, FOXP3+ Tregs, especially ICOS+ FOXP3+ Tregs, contribute to the immunosuppressive HCC microenvironment. High tumour-infiltrating Tregs are thought to be an unfavourable prognostic indicator of HCC.

MeSH terms

  • Adult
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / metabolism
  • Carcinoma, Hepatocellular / immunology
  • Carcinoma, Hepatocellular / pathology*
  • Female
  • Forkhead Transcription Factors / metabolism*
  • Humans
  • Inducible T-Cell Co-Stimulator Protein / metabolism*
  • Liver Neoplasms / immunology
  • Liver Neoplasms / pathology*
  • Lymphocytes, Tumor-Infiltrating
  • Male
  • Middle Aged
  • Prognosis
  • Random Allocation
  • Survival Analysis
  • T-Lymphocytes, Regulatory / immunology*
  • Tumor Microenvironment


  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • ICOS protein, human
  • Inducible T-Cell Co-Stimulator Protein