Interleukin-6/STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy.
Interleukin-6/STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy.
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DOI：
10.1111/cas.13332
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发表时间：
2017-10
期刊：
影响因子：
5.7
通讯作者：
Taketomi A
中科院分区：
文献类型：
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作者：
Kitamura H;Ohno Y;Toyoshima Y;Ohtake J;Homma S;Kawamura H;Takahashi N;Taketomi A
克服肿瘤微环境中的免疫抑制状态是提高癌症免疫治疗效果的关键问题。白细胞介素（IL）-6是一种多效性细胞因子，在荷瘤宿主中大量产生。已有研究表明IL-6通过激活信号转导子和转录激活子3（STAT 3）抑制树突状细胞（DC）的抗原提呈能力。因此，我们专注于IL-6/STAT 3信号级联对人DC的精确作用以及随后诱导抗肿瘤T细胞免疫应答。与外周血单核细胞相比，从结直肠癌组织中分离的肿瘤浸润性CD 11b + CD 11 c+细胞显示出强烈的IL-6基因诱导，人类白细胞抗原（HLA）-DR的表面表达下调，T细胞刺激能力减弱，表明肿瘤微环境抑制抗肿瘤效应细胞。体外实验显示，IL-6介导的STAT 3活化降低了CD 14+单核细胞衍生DC上HLA-DR的表面表达。此外，我们证实了环氧合酶2、溶酶体蛋白酶和过氧化物酶活性参与了IL-6介导的人DC表面HLA II类表达水平的下调。这些发现表明，肿瘤微环境中IL-6介导的STAT 3激活抑制了DC的功能成熟以激活效应T细胞，从而阻断了癌症中抗肿瘤免疫的引入。因此，我们在这篇综述中提出，阻断DC中的IL-6/STAT 3信号通路和靶分子可能是提高癌症患者免疫治疗疗效的一种有前途的策略。
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.
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影响因子：
--
作者：
Heo TH;Wahler J;Suh N
通讯作者：
Suh N
DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
158.5
作者：
Hunder, Naomi N.;Wallen, Herschel;Yee, Cassian
通讯作者：
Yee, Cassian
影响因子：
11.5
作者：
Angevin, Eric;Tabernero, Josep;Kurzrock, Razelle
通讯作者：
Kurzrock, Razelle
影响因子：
64.8
作者：
HIRANO, T;YASUKAWA, K;KISHIMOTO, T
通讯作者：
KISHIMOTO, T