Identification of a FOXP3(+)CD3(+)CD56(+) population with immunosuppressive function in cancer tissues of human hepatocellular carcinoma

Sci Rep. 2015 Oct 6;5:14757. doi: 10.1038/srep14757.

Abstract

The liver resident lymphoid population is featured by the presence of a large number of CD3(+)CD56(+) cells referred as natural T cells. In human hepatocellular carcinoma (HCC) patients, the natural T cells were found to be sharply decreased in tumor (5.871 ± 3.553%) versus non-tumor (14.02 ± 6.151%) tissues. More intriguingly, a substantial fraction of the natural T cells (22.76 ± 18.61%) assumed FOXP3 expression. These FOXP3-expressing CD3(+)CD56(+) cells lost the expression of IFN-γ and perforin, which are critical for the effector function of natural T cells. On the other hand, they acquired surface expression of CD25 and CTLA-4 typically found in regulatory T (Treg) cells. Consistent with the phenotypic conversion, they imposed an inhibitory effect on anti-CD3-induced proliferation of naive T cells. Further studies demonstrated that transforming growth factor β1 (TGF-β1) could effectively induce FOXP3 expression in CD3(+)CD56(+) cells and the cells were thus endowed with a potent immunosuppressive capacity. Finally, Kaplan-Meier analysis revealed that the relative abundance of FOXP3-expressing CD3(+)CD56(+) cells in tumor tissues was significantly correlated with the survival of HCC patients. In conclusion, the present study identified a new type of regulatory immune cells whose emergence in liver cancer tissues may contribute to tumor progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers / metabolism
  • CD3 Complex / genetics
  • CD3 Complex / immunology*
  • CD56 Antigen / genetics
  • CD56 Antigen / immunology*
  • CTLA-4 Antigen / genetics
  • CTLA-4 Antigen / immunology
  • Carcinoma, Hepatocellular / diagnosis
  • Carcinoma, Hepatocellular / immunology*
  • Carcinoma, Hepatocellular / mortality
  • Carcinoma, Hepatocellular / pathology
  • Cell Lineage / drug effects
  • Cell Lineage / immunology
  • Cellular Reprogramming / immunology
  • Female
  • Flow Cytometry
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology*
  • Gene Expression
  • Humans
  • Immunophenotyping
  • Interleukin-2 Receptor alpha Subunit / genetics
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Liver Neoplasms / diagnosis
  • Liver Neoplasms / immunology*
  • Liver Neoplasms / mortality
  • Liver Neoplasms / pathology
  • Male
  • Middle Aged
  • Primary Cell Culture
  • Survival Analysis
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / pathology
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / pathology
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / immunology
  • Transforming Growth Factor beta1 / pharmacology

Substances

  • Biomarkers
  • CD3 Complex
  • CD56 Antigen
  • CTLA-4 Antigen
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • IL2RA protein, human
  • Interleukin-2 Receptor alpha Subunit
  • NCAM1 protein, human
  • Transforming Growth Factor beta1