文章目录

eIF5B驱动PD-L1在肺癌中的综合应激反应依赖性翻译

原文发布日期：2020-04-20

英文摘要：

摘要翻译：

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文章：

eIF5B驱动PD-L1在肺癌中的综合应激反应依赖性翻译

eIF5B drives integrated stress response-dependent translation of PD-L1 in lung cancer

原文发布日期：2020-04-20

英文摘要：

Cancer cells express high levels of programmed death ligand 1 (PD-L1), a ligand of the programmed cell death protein 1 (PD-1) receptor on T cells, allowing tumors to suppress T cell activity. Clinical trials utilizing antibodies that disrupt the PD-1/PD-L1 checkpoint have yielded remarkable results, with anti-PD-1 immunotherapy approved as a first-line therapy for patients with lung cancer. We used CRISPR-based screening to identify regulators of PD-L1 in human lung cancer cells, revealing potent induction of PD-L1 upon disruption of heme biosynthesis. Impairment of heme production activates the integrated stress response, allowing bypass of inhibitory upstream open reading frames in the PD-L1 5′ untranslated region, resulting in enhanced PD-L1 translation and suppression of anti-tumor immunity. We demonstrate that integrated stress-response-dependent PD-L1 translation requires the translation initiation factor eIF5B. eIF5B overexpression, which is frequent in lung adenocarcinomas and associated with poor prognosis, is sufficient to induce PD-L1. These findings illuminate mechanisms of immune checkpoint activation and identify targets for therapeutic intervention.

摘要翻译：

肿瘤细胞高表达程序性死亡配体1（PD-L1），该配体是程序性细胞死亡蛋白-1受体（PD-1）在T细胞上的结合位点，使肿瘤抑制T细胞活动。临床试验使用破坏PD-1/PD-L1检点的抗体取得了显著成果，抗PD-1免疫疗法已被批准为针对肺癌患者的一线治疗方案。我们运用CRISPR筛选法识别了人类肺癌细胞中调控PD-L1的调节因素，发现当干扰卟啉生物合成时，PD-L1被强烈诱导。卟啉产量受损激活整合应激响应，使抑制性上支链启动子在PD-L1 5' untranslated region（UTR）中的阻挡得以ypass，从而增强PD-L1的翻译，抑制肿瘤免疫反应。我们证明了依赖整合应激响应的PD-L1翻译需要翻译起始因子eIF5B。eIF5B过表达是肺癌腺癌中常见的特征，并与预后不良相关联。eIF5B过表达足以诱导PD-L1的表达。这些发现阐明了免疫检点激活机制，识别出新的治疗靶点。