期刊
CANCER SCIENCE
卷 108, 期 10, 页码 1947-1952出版社
WILEY
DOI: 10.1111/cas.13332
关键词
Cancer immunotherapy; dendritic cell; immunosuppression; interleukin-6; STAT 3
类别
资金
- Japan Society for the Promotion of Science (JSPS) [25460584, 16K10526]
- Platform Project for Supporting Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan
- Japan Agency for Medical Research and Development (AMED)
- Joint Research Program of the Institute for Genetic Medicine, Hokkaido University
- Grants-in-Aid for Scientific Research [16K10526, 25460584, 15K08416] Funding Source: KAKEN
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. Invitro 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.
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