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

Authors

  • Yanmei Han,

    1. National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, China
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    • These authors contributed equally to this work.

  • Zhubo Chen,

    1. National Key Laboratory of Medical Molecular Biology and Department of Immunology, Chinese Academy of Medical Sciences, Beijing, China
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    • These authors contributed equally to this work.

  • Yuan Yang,

    1. Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
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    • These authors contributed equally to this work.

  • Zhengping Jiang,

    1. National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, China
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  • Yan Gu,

    1. National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, China
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  • Yangfang Liu,

    1. National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, China
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  • Chuan Lin,

    1. Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
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  • Zeya Pan,

    1. Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
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  • Yizhi Yu,

    1. National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, China
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  • Minghong Jiang,

    1. National Key Laboratory of Medical Molecular Biology and Department of Immunology, Chinese Academy of Medical Sciences, Beijing, China
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  • Weiping Zhou,

    1. Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
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    • These two authors share senior authorship.

  • Xuetao Cao

    Corresponding author
    1. National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, China
    2. National Key Laboratory of Medical Molecular Biology and Department of Immunology, Chinese Academy of Medical Sciences, Beijing, China
    • Address reprint requests to: Xuetao Cao, M.D., Ph.D., National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China. E-mail: caoxt@immunol.org; fax: +86 21 6538 2502.

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    • These two authors share senior authorship.


  • This work was supported by grants from the MOST 125 Major Project of China (2012ZX10002014-001 and 2012ZX10002010), the National Key Basic Research Program of China (2011CB965202, 2013CB530503, and 2013CB944903), the National Natural Science Foundation of China (31170843), and the Foundation for the Author of National Excellent Doctoral Dissertation of China (201071).

  • Potential conflict of interest : Nothing to report.

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. (Hepatology 2014;59:567–579)

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