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Interleukin-6/STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy

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Title: Interleukin-6/STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy
Authors: Kitamura, Hidemitsu Browse this author →KAKEN DB
Ohno, Yosuke Browse this author
Toyoshima, Yujiro Browse this author
Ohtake, Junya Browse this author
Homma, Shigenori Browse this author →KAKEN DB
Kawamura, Hideki Browse this author →KAKEN DB
Takahashi, Norihiko Browse this author
Taketomi, Akinobu Browse this author →KAKEN DB
Keywords: Cancer immunotherapy
dendritic cell
Issue Date: Oct-2017
Publisher: John Wiley & Sons
Journal Title: Cancer Science
Volume: 108
Issue: 10
Start Page: 1947
End Page: 1952
Publisher DOI: 10.1111/cas.13332
Abstract: Overcoming the immunosuppressive state in tumor microenvironments is a critical issue for improving the efficacy of cancer immunotherapy. Interleukin (IL)-6, a pleiotropic cytokine, is highly produced in the tumor-bearing host. Previous studies have indicated that IL-6 suppresses the antigen presentation ability of dendritic cells (DC) through activation of signal transducer and activator of transcription 3 (STAT3). Thus, we focused on the precise effect of the IL-6/STAT3 signaling cascade on human DC and the subsequent induction of antitumor T cell immune responses. Tumor-infiltrating CD11b+CD11c+ cells isolated from colorectal cancer tissues showed strong induction of the IL-6 gene, downregulated surface expression of human leukocyte antigen (HLA)-DR, and an attenuated T cell-stimulating ability compared with those from peripheral blood mononuclear cells, suggesting that the tumor microenvironment suppresses antitumor effector cells. In vitro experiments revealed that IL-6-mediated STAT3 activation reduced surface expression of HLA-DR on CD14+ monocyte-derived DC. Moreover, we confirmed that cyclooxygenase 2, lysosome protease and arginase activities were involved in the IL-6-mediated downregulation of the surface expression levels of HLA class II on human DC. These findings suggest that IL-6-mediated STAT3 activation in the tumor microenvironment inhibits functional maturation of DC to activate effector T cells, blocking introduction of antitumor immunity in cancers. Therefore, we propose in this review that blockade of the IL-6/STAT3 signaling pathway and target molecules in DC may be a promising strategy to improve the efficacy of immunotherapies for cancer patients.
Type: article
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)

Submitter: 北村 秀光

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