title: Human CD14+ CTLA-4+ regulatory dendritic cells suppress T-cell response by cytotoxic T-lymphocyte antigen-4-dependent IL-10 and indoleamine-2,3-dioxygenase production in hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with limited therapeutic options. HCC-induced immunosuppression often leads to ineffectiveness of immuno-promoting therapies. Currently, suppressing the suppressors has become the potential strategy for cancer immunotherapy. So, figuring out the immunosuppressive mechanisms induced and employed by HCC will be helpful to the design and application of HCC immunotherapy. Here, we identified one new subset of human CD14(+) CTLA-4(+) regulatory dendritic cells (CD14(+) DCs) in HCC patients, representing ∼13% of peripheral blood mononuclear cells. CD14(+) DCs significantly suppress T-cell response in vitro through interleukin (IL)-10 and indoleamine-2,3-dioxygenase (IDO). Unexpectedly, CD14(+) DCs expressed high levels of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1, and CTLA-4 was found to be essential to IL-10 and IDO production. So, we identified a novel human tumor-induced regulatory DC subset, which suppresses antitumor immune response through CTLA-4-dependent IL-10 and IDO production, thus indicating the important role of nonregulatory T-cell-derived CTLA-4 in tumor-immune escape or immunosuppression.
  
  
  CONCLUSIONS
  These data outline one mechanism for HCC to induce systemic immunosuppression by expanding CD14(+) DCs, which may contribute to HCC progression. This adds new insight to the mechanism for HCC-induced immunosuppression and may also provide a previously unrecognized target of immunotherapy for HCC.
authors: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, China.
authors: Yanmei
authors: Y
authors: Han
authors: Zhubo
authors: Z
authors: Chen
authors: Yuan
authors: Y
authors: Yang
authors: Zhengping
authors: Z
authors: Jiang
authors: Yan
authors: Y
authors: Gu
authors: Yangfang
authors: Y
authors: Liu
authors: Chuan
authors: C
authors: Lin
authors: Zeya
authors: Z
authors: Pan
authors: Yizhi
authors: Y
authors: Yu
authors: Minghong
authors: M
authors: Jiang
authors: Weiping
authors: W
authors: Zhou
authors: Xuetao
authors: X
authors: Cao
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D039481:CD11b Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D060908:CTLA-4 Antigen / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D003713:Dendritic Cells / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D007167:Immunotherapy; D066298:In Vitro Techniques; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000473:pathology; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D055815:Young Adult
chemical_list: D039481:CD11b Antigen; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018950:Lipopolysaccharide Receptors; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D016753:Interleukin-10