Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR.
Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR.
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DOI：
10.18632/oncotarget.1637
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发表时间：
2014-02-28
期刊：
影响因子：
--
通讯作者：
Platten M
中科院分区：
文献类型：
--
作者：
Litzenburger UM;Opitz CA;Sahm F;Rauschenbach KJ;Trump S;Winter M;Ott M;Ochs K;Lutz C;Liu X;Anastasov N;Lehmann I;Höfer T;von Deimling A;Wick W;Platten M
吲哚胺 - 2,3 - 双加氧酶（IDO）抑制剂基于临床前研究中其恢复抗肿瘤免疫的能力已进入临床试验。然而，导致人类肿瘤中IDO组成性表达的机制在很大程度上是未知的。在此我们分析了介导人类癌症中IDO组成性表达的通路。IDO阳性肿瘤细胞和组织显示出STAT3的基础磷酸化和乙酰化，这通过蛋白质印迹和免疫沉淀得以证明。使用小干扰RNA和/或药物抑制剂抑制白细胞介素 - 6（IL - 6）或STAT3可降低IDO的信使核糖核酸（mRNA）和蛋白质表达以及犬尿氨酸的形成。反过来，IDO酶活性激活了芳香烃受体（AHR），这通过AHR靶基因的诱导得以显示。IDO介导的AHR激活诱导了IL - 6表达，而AHR的抑制或敲低降低了IL - 6表达。因此，IDO活性通过自分泌的AHR - IL - 6 - STAT3信号回路维持其自身表达。在存在表达IDO的人类癌细胞的情况下进行的混合淋巴细胞反应中，抑制AHR - IL - 6 - STAT3信号回路恢复了T细胞增殖。确定在人类癌症中维持IDO表达的IDO - AHR - IL - 6 - STAT3信号回路揭示了抑制这一促进人类癌症免疫抑制的核心通路的新治疗靶点。其成员IDO、STAT3和AHR靶基因CYP1B1的高表达与肺癌患者无复发生存率降低相关这一发现强调了IDO - AHR - IL - 6 - STAT3转录回路的相关性。
Indoleamine-2,3-dioxygenase (IDO) inhibitors have entered clinical trials based on their ability to restore anti-tumor immunity in preclinical studies. However, the mechanisms leading to constitutive expression of IDO in human tumors are largely unknown. Here we analyzed the pathways mediating constitutive IDO expression in human cancer. IDO-positive tumor cells and tissues showed basal phosphorylation and acetylation of STAT3 as evidenced by western blotting and immunoprecipitation. Inhibition of IL-6 or STAT3 using siRNA and/or pharmacological inhibitors reduced IDO mRNA and protein expression as well as kynurenine formation. In turn, IDO enzymatic activity activated the AHR as shown by the induction of AHR target genes. IDO-mediated AHR activation induced IL-6 expression, while inhibition or knockdown of the AHR reduced IL-6 expression. IDO activity thus sustains its own expression via an autocrine AHR–IL-6–STAT3 signaling loop. Inhibition of the AHR–IL-6–STAT3 signaling loop restored T-cell proliferation in mixed leukocyte reactions performed in the presence of IDO-expressing human cancer cells. Identification of the IDO-AHR-IL-6-STAT3 signaling loop maintaining IDO expression in human cancers reveals novel therapeutic targets for the inhibition of this core pathway promoting immunosuppression of human cancers. The relevance of the IDO-AHR-IL-6-STAT3 transcriptional circuit is underscored by the finding that high expression of its members IDO, STAT3 and the AHR target gene CYP1B1 is associated with reduced relapse-free survival in lung cancer patients.
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