title: A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Medizinische Hochschule Hannover, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Hoechst
authors.forename: Lars A
authors.initials: LA
authors.lastname: Ormandy
authors.forename: Matthias
authors.initials: M
authors.lastname: Ballmaier
authors.forename: Frank
authors.initials: F
authors.lastname: Lehner
authors.forename: Christine
authors.initials: C
authors.lastname: Krüger
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Tim F
authors.initials: TF
authors.lastname: Greten
authors.forename: Firouzeh
authors.initials: F
authors.lastname: Korangy
mesh_terms: D000368:Aged; D001119:Arginase / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006684:HLA-DR Antigens / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008113:Liver Neoplasms / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D022423:Myeloid Cells / Q000145:classification / Q000166:cytology / Q000276:immunology*
chemical_list: D015415:Biomarkers; D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006684:HLA-DR Antigens; C508609:IL10 protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D018950:Lipopolysaccharide Receptors; D016753:Interleukin-10; D001119:Arginase