Inhibition of Nr4a Receptors Enhances Antitumor Immunity by Breaking Treg-Mediated Immune Tolerance
Inhibition of Nr4a Receptors Enhances Antitumor Immunity by Breaking Treg-Mediated Immune Tolerance
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DOI：
10.1158/0008-5472.can-17-3102
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发表时间：
2018-06-01
期刊：
影响因子：
11.2
通讯作者：
Yoshimura, Akihiko
中科院分区：
文献类型：
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作者：
Hibino, Sana;Chikuma, Shunsuke;Yoshimura, Akihiko
调节性T细胞（Treg）向肿瘤组织的浸润增强对癌症患者有害，并且与预后不良密切相关，因为它们会产生抑制抗肿瘤免疫反应的免疫抑制状态。因此，在考虑癌症免疫疗法时，打破Treg介导的免疫耐受是重要的。在这里，我们表明，Nr 4a核受体，维持Treg基因程序的关键转录因子，有助于Treg介导的抑制肿瘤微环境中的抗肿瘤免疫。在移植模型中缺乏特异性TcB中的Nr 4a 1和Nr 4a 2基因的小鼠表现出对肿瘤生长的抵抗力，而没有表现出任何严重的全身性自身免疫。化疗药物喜树碱和一种常见的环氧合酶-2抑制剂被发现抑制转录活性和诱导的Nr 4a因子，它们协同发挥抗肿瘤作用。Nr 4a因子的遗传失活或药理学抑制释放了CD 8+细胞毒性T细胞的效应子活性，并诱发了有效的抗肿瘤免疫应答。这些发现表明，Treg中Nr 4a的失活会破坏对癌症的免疫耐受，Nr 4a活性的药理学调节可能是一种针对免疫抑制肿瘤微环境的新型癌症治疗策略。意义：这项研究揭示了Nr 4a转录因子在Treg介导的抗肿瘤免疫耐受中的作用，对于开发有效的抗癌疗法可能具有治疗意义。(C)2018年AACR。
Enhanced infiltration of regulatory T cells (Treg) into tumor tissue is detrimental to patients with cancer and is closely associated with poor prognosis as they create an immunosuppressive state that suppresses antitumor immune responses. Therefore, breaking Treg-mediated immune tolerance is important when considering cancer immunotherapy. Here, we show that the Nr4a nuclear receptors, key transcription factors maintaining Treg genetic programs, contribute to Treg-mediated suppression of antitumor immunity in the tumor microenvironment. Mice lacking Nr4a1 and Nr4a2 genes specifically in Tregs showed resistance to tumor growth in transplantation models without exhibiting any severe systemic autoimmunity. The chemotherapeutic agent camptothecin and a common cyclooxygenase-2 inhibitor were found to inhibit transcriptional activity and induction of Nr4a factors, and they synergistically exerted antitumor effects. Genetic inactivation or pharmacologic inhibition of Nr4a factors unleashed effector activities of CD8+ cytotoxic T cells and evoked potent antitumor immune responses. These findings demonstrate that inactivation of Nr4a in Tregs breaks immune tolerance toward cancer, and pharmacologic modulation of Nr4a activity may be a novel cancer treatment strategy targeting the immunosuppressive tumor microenvironment.Significance: This study reveals the role of Nr4a transcription factors in Treg-mediated tolerance to antitumor immunity, with possible therapeutic implications for developing effective anticancer therapies. (C) 2018 AACR.