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

タイトル	en 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
作成者	en Ohno, Yosuke en Kitamura, Hidemitsu NRID 1000040360531 en Takahashi, Norihiko en Ohtake, Junya en Kaneumi, Shun en Sumida, Kentaro en Homma, Shigenori NRID 1000030533674 en Kawamura, Hideki en Minagawa, Nozomi en Shibasaki, Susumu en Taketomi, Akinobu NRID 1000070363364
アクセス権	open access
権利情報	en The final publication is available at Springer via http://dx.doi.org/10.1007/s00262-015-1791-4
主題	Other en Dendritic cells Other en Antigen presentation Other en HLA class II Other en IL-12 Other en Helper T cells NDC 490
内容注記	Abstract en 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.
出版者	en Springer
日付	Issued2016-02
言語	eng
資源タイプ	journal article
出版タイプ	AM
資源識別子	HDL http://hdl.handle.net/2115/64455
関連	isVersionOf DOI https://doi.org/10.1007/s00262-015-1791-4 PMID 26759006
収録誌情報	PISSN 0340-7004 en Cancer immunology, immunotherapy 巻65 号2 開始ページ193 終了ページ204
ファイル	fulltext manuscript.pdf 4.26 MB (application/pdf) Issued2016-02
コンテンツ更新日時	2023-07-26