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

• Ohno, Yosuke

• Kitamura, Hidemitsu

• Takahashi, Norihiko

• Ohtake, Junya

• Kaneumi, Shun

• Sumida, Kentaro

• Homma, Shigenori

• Kawamura, Hideki

• Minagawa, Nozomi

• Shibasaki, Susumu

• Taketomi, Akinobu

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.

Journal

• Cancer immunology, immunotherapy

  Cancer immunology, immunotherapy 65 (2), 193-204, 2016-02

  Springer

Keywords

• Dendritic cells
• Antigen presentation
• HLA class II
• IL-12
• Helper T cells

Details

• CRID: 1050282813996120320
• NII Article ID: 120006581487
• HANDLE: 2115/64455
• ISSN: 03407004
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • CiNii Articles