A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells

Gastroenterology. 2008 Jul;135(1):234-43. doi: 10.1053/j.gastro.2008.03.020. Epub 2008 Mar 21.


Background & aims: Several studies have shown that development of hepatocellular carcinoma (HCC) generates a number of immune suppressive mechanisms in these patients. Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells that have been shown to inhibit T-cell responses in tumor-bearing mice, but little is known about these cells in humans owing to a lack of specific markers. In this study, we have investigated the frequency and function of a new population of MDSC denoted here as CD14(+)HLA-DR(-/low) in HCC patients. We have also identified a novel, MDSC-mediated immune regulatory pathway in these patients.

Methods: We have directly isolated and characterized MDSCs for phenotype and function from peripheral blood (n = 111) and tumor (n = 12) of patients with HCC.

Results: The frequency of CD14(+)HLA-DR(-/low) cells in peripheral blood mononuclear cells (PBMC) from HCC patients was significantly increased in comparison with healthy controls. CD14(+) HLA-DR(-/low) cells were unable to stimulate an allogeneic T-cell response, suppressed autologous T-cell proliferation, and had high arginase activity, a hallmark characteristic of MDSC. Most important, CD14(+)HLA-DR(-/low) cells from HCC patients induced a CD4(+)CD25(+)Foxp3(+) regulatory T-cell population when cocultured with autologous T cells.

Conclusion: CD14(+)HLA-DR(-/low) cells are a new population of MDSC increased in blood and tumor of HCC patients. We propose a new mechanism by which MDSC exert their immunosuppressive function, through the induction of CD4(+)CD25(+)Foxp3(+) regulatory T cells in cocultured CD4(+) T cells. Understanding the mechanism of action of MDSC in HCC patients is important in the design of effective immunotherapeutic protocols.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Arginase / metabolism
  • Biomarkers / metabolism
  • CD4 Antigens / metabolism
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology*
  • Carcinoma, Hepatocellular / immunology*
  • Carcinoma, Hepatocellular / metabolism
  • Cell Communication / immunology
  • Cell Division / immunology
  • Cells, Cultured
  • Female
  • Flow Cytometry
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • HLA-DR Antigens / genetics
  • HLA-DR Antigens / metabolism
  • Humans
  • Immune Tolerance / immunology*
  • Immunophenotyping
  • Interleukin-10 / metabolism
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Lipopolysaccharide Receptors / metabolism
  • Liver Neoplasms / immunology*
  • Liver Neoplasms / metabolism
  • Male
  • Middle Aged
  • Myeloid Cells / classification
  • Myeloid Cells / cytology
  • Myeloid Cells / immunology*


  • Biomarkers
  • CD4 Antigens
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • HLA-DR Antigens
  • IL10 protein, human
  • Interleukin-2 Receptor alpha Subunit
  • Lipopolysaccharide Receptors
  • Interleukin-10
  • Arginase