IL-6 down-regulates HLA class II expression and IL-12 production of human dendritic cells to impair activation of antigen-specific CD4+ T cells

Yosuke Ohno, Hidemitsu Kitamura, Norihiko Takahashi, Junya Ohtake, Shun Kaneumi, Kentaro Sumida, Shigenori Homma, Hideki Kawamura, Nozomi Minagawa, Susumu Shibasaki, Akinobu Taketomi

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26 Citations (Scopus)

Abstract

Immunosuppression in tumor microenvironments critically affects the success of cancer immunotherapy. Here, we focused on the role of interleukin (IL)-6/signal transducer and activator of transcription (STAT3) signaling cascade in immune regulation by human dendritic cells (DCs). IL-6-conditioned monocyte-derived DCs (MoDCs) impaired the presenting ability of cancer-related antigens. Interferon (IFN)-γ production attenuated by CD4+ T cells co-cultured with IL-6-conditioned MoDCs corresponded with decreased DC IL-12p70 production. Human leukocyte antigen (HLA)-DR and CD86 expression was significantly reduced in CD11b+CD11c+ cells obtained from peripheral blood mononuclear cells (PBMCs) of healthy donors by IL-6 treatment and was STAT3 dependent. Arginase-1 (ARG1), lysosomal protease, cathepsin L (CTSL), and cyclooxygenase-2 (COX2) were involved in the reduction of surface HLA-DR expression. Gene expressions of ARG1, CTSL, COX2, and IL6 were higher in tumor-infiltrating CD11b+CD11c+ cells compared with PBMCs isolated from colorectal cancer patients. Expression of surface HLA-DR and CD86 on CD11b+CD11c+ cells was down-regulated, and T cell-stimulating ability was attenuated compared with PBMCs, suggesting that an immunosuppressive phenotype might be induced by IL-6, ARG1, CTSL, and COX2 in tumor sites of colorectal cancer patients. There was a relationship between HLA-DR expression levels in tumor tissues and the size of CD4+ T and CD8+ T cell compartments. Our findings indicate that IL-6 causes a dysfunction in human DCs that activates cancer antigen-specific Th cells, suggesting that blocking the IL-6/STAT3 signaling pathway might be a promising strategy to improve cancer immunotherapy.

Original languageEnglish
Pages (from-to)193-204
Number of pages12
JournalCancer Immunology, Immunotherapy
Volume65
Issue number2
DOIs
Publication statusPublished - 01-02-2016

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

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    Ohno, Y., Kitamura, H., Takahashi, N., Ohtake, J., Kaneumi, S., Sumida, K., Homma, S., Kawamura, H., Minagawa, N., Shibasaki, S., & Taketomi, A. (2016). IL-6 down-regulates HLA class II expression and IL-12 production of human dendritic cells to impair activation of antigen-specific CD4+ T cells. Cancer Immunology, Immunotherapy, 65(2), 193-204. https://doi.org/10.1007/s00262-015-1791-4