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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 | immunosuppression | interleukin-6 | STAT 3 |
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. |
Rights: | http://creativecommons.org/licenses/by-nc/4.0/ |
Type: | article |
URI: | http://hdl.handle.net/2115/67657 |
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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Submitter: 北村 秀光
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