The Nuclear Orphan Receptor NR2F6 Is a Central Checkpoint for Cancer Immune Surveillance.
The Nuclear Orphan Receptor NR2F6 Is a Central Checkpoint for Cancer Immune Surveillance.
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DOI：
10.1016/j.celrep.2015.08.035
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发表时间：
2015-09-29
期刊：
影响因子：
8.8
通讯作者：
Baier G
中科院分区：
文献类型：
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作者：
Hermann-Kleiter N;Klepsch V;Wallner S;Siegmund K;Klepsch S;Tuzlak S;Villunger A;Kaminski S;Pfeifhofer-Obermair C;Gruber T;Wolf D;Baier G
核受体亚家族2，F组，成员6(NR2F6)是核受体超家族的孤儿成员。在这里，我们表明，在转基因小鼠前列腺癌模型中，基因消融Nr2f6显著提高了存活率。此外，Nr2f6−/−小鼠自发排斥移植的肿瘤，并针对肿瘤再攻击形成宿主保护性免疫记忆。同时，CD4+和CD8+T细胞的频率增加，肿瘤部位白细胞介素2和干扰素γ的表达水平也较高。从机制上讲，CD4+和CD8+T细胞固有的NR2F6可以直接抑制NFAT/AP-1复合体对白细胞介素2和干扰素γ细胞因子启动子的作用，减弱它们的转录阈值。过继将Nr2f6缺陷的T细胞转移到荷瘤免疫活性小鼠中足以延缓肿瘤的生长。总之，这将NR2F6定义为效应器T细胞中的细胞内免疫检查点，控制着抗癌免疫的幅度。基因消融Nr2F6诱导免疫介导的肿瘤监测Nr2F6−/−小鼠表现出有利于抗肿瘤反应的免疫环境NR2F6抑制CD4+和CD8+效应T细胞中关键细胞因子的转录NR2F6控制肿瘤免疫的幅度免疫检查点阻断已成为一种有效的癌症免疫治疗策略。在这里，赫尔曼-克莱特等人。展示核孤儿受体NRF26在肿瘤免疫监测中的作用，有效地识别控制抗癌免疫幅度的效应T细胞中的细胞内免疫检查点。
Nuclear receptor subfamily 2, group F, member 6 (NR2F6) is an orphan member of the nuclear receptor superfamily. Here, we show that genetic ablation of Nr2f6 significantly improves survival in the murine transgenic TRAMP prostate cancer model. Furthermore, Nr2f6−/− mice spontaneously reject implanted tumors and develop host-protective immunological memory against tumor rechallenge. This is paralleled by increased frequencies of both CD4+ and CD8+ T cells and higher expression levels of interleukin 2 and interferon γ at the tumor site. Mechanistically, CD4+ and CD8+ T cell-intrinsic NR2F6 acts as a direct repressor of the NFAT/AP-1 complex on both the interleukin 2 and the interferon γ cytokine promoters, attenuating their transcriptional thresholds. Adoptive transfer of Nr2f6-deficient T cells into tumor-bearing immunocompetent mice is sufficient to delay tumor outgrowth. Altogether, this defines NR2F6 as an intracellular immune checkpoint in effector T cells, governing the amplitude of anti-cancer immunity. Genetic ablation of Nr2f6 induces immune-mediated cancer surveillance Nr2f6−/− mice display an immune contexture favoring anti-tumor responses NR2F6 represses transcription of key cytokines in CD4+ and CD8+ effector T cells NR2F6 controls the amplitude of tumor immunity Immune checkpoint blockade has emerged as an effective cancer immunotherapy strategy. Here, Hermann-Kleiter et al. demonstrate a role for the nuclear orphan receptor NRF26 in tumor immune surveillance, effectively identifying an intracellular immune checkpoint in effector T cells that governs the amplitude of anti-cancer immunity.