| Title: | 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 |
| Authors: | Ohno, Yosuke Browse this author |
| Kitamura, Hidemitsu Browse this author →KAKEN DB |
| Takahashi, Norihiko Browse this author |
| Ohtake, Junya Browse this author |
| Kaneumi, Shun Browse this author |
| Sumida, Kentaro Browse this author |
| Homma, Shigenori Browse this author →KAKEN DB |
| Kawamura, Hideki Browse this author |
| Minagawa, Nozomi Browse this author |
| Shibasaki, Susumu Browse this author |
| Taketomi, Akinobu Browse this author →KAKEN DB |
| Keywords: | Dendritic cells |
| Antigen presentation |
| HLA class II |
| IL-12 |
| Helper T cells |
| Issue Date: | Feb-2016 |
| Publisher: | Springer |
| Journal Title: | Cancer immunology, immunotherapy |
| Volume: | 65 |
| Issue: | 2 |
| Start Page: | 193 |
| End Page: | 204 |
| Publisher DOI: | 10.1007/s00262-015-1791-4 |
| PMID: | 26759006 |
| 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. |
| Rights: | The final publication is available at Springer via http://dx.doi.org/10.1007/s00262-015-1791-4 |
| Type: | article (author version) |
| URI: | http://hdl.handle.net/2115/64455 |
| Appears in Collections: | 遺伝子病制御研究所 (Institute for Genetic Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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