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

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 et al.

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

Permalink : https://hdl.handle.net/2115/64455

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アクセス権	open access
URI	https://hdl.handle.net/2115/64455
タイトル	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
著者	Ohno, Yosuke ; Kitamura, Hidemitsu ; Takahashi, Norihiko ; Ohtake, Junya ; Kaneumi, Shun ; Sumida, Kentaro ; Homma, Shigenori ; Kawamura, Hideki ; Minagawa, Nozomi ; Shibasaki, Susumu ; Taketomi, Akinobu
著者名 Ohno, Yosuke
e-Rad_Researcher 40360531 著者名 Kitamura, Hidemitsu
著者名 Takahashi, Norihiko
著者名 Ohtake, Junya
著者名 Kaneumi, Shun
著者名 Sumida, Kentaro
e-Rad_Researcher 30533674 著者名 Homma, Shigenori
著者名 Kawamura, Hideki
著者名 Minagawa, Nozomi
著者名 Shibasaki, Susumu
e-Rad_Researcher 70363364 著者名 Taketomi, Akinobu
言語	英語
キーワード	Dendritic cells
	Antigen presentation
	HLA class II
	IL-12
	Helper T cells
発行日	2016-02
出版者	Springer
収録物名	Cancer immunology, immunotherapy
巻(号)	65(2)
ページ	193-204
抄録	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.
資源タイプ	学術雑誌論文
出版タイプ	Accepted Manuscript
権利情報	The final publication is available at Springer via http://dx.doi.org/10.1007/s00262-015-1791-4
PISSN	0340-7004
関連情報	PMID 26759006
関連情報 (isVersionOf)	出版社版DOI https://doi.org/10.1007/s00262-015-1791-4