Translational control of tumor immune escape via the eIF4F-STAT1-PD-L1 axis in melanoma
Translational control of tumor immune escape via the eIF4F-STAT1-PD-L1 axis in melanoma
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DOI：
10.1038/s41591-018-0217-1
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发表时间：
2018-12-01
期刊：
影响因子：
82.9
通讯作者：
Robert, Caroline
中科院分区：
文献类型：
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作者：
Cerezo, Michael;Guemiri, Ramdane;Robert, Caroline
通过阻断抑制性检查点（例如程序性死亡配体-1（PD-L1）和程序性死亡-1（PD-1）受体之间的相互作用）来防止肿瘤细胞的免疫逃逸是一种强大的抗癌方法。然而，许多患者对检查站封锁没有反应。肿瘤PD-L1表达是一种潜在的疗效生物标志物，但其调控的复杂机制尚不完全清楚。在这里，我们表明，真核翻译起始复合物，eIF 4F，结合5'帽的mRNA，调节干扰素-γ诱导的PD-L1在癌细胞上的表面表达，通过调节翻译的mRNA编码的信号转导和转录激活因子1（STAT 1）转录因子。eIF 4F复合物的形成与人黑色素瘤对免疫疗法的应答相关。eIF 4A（eIF 4F的RNA解旋酶组分）的药理学抑制通过PD-L1下调产生强大的抗肿瘤免疫介导作用。因此，eIF 4A抑制剂作为抗癌药物开发，也可以作为癌症免疫疗法。
Preventing the immune escape of tumor cells by blocking inhibitory checkpoints, such as the interaction between programmed death ligand-1 (PD-L1) and programmed death-1 (PD-1) receptor, is a powerful anticancer approach. However, many patients do not respond to checkpoint blockade. Tumor PD-L1 expression is a potential efficacy biomarker, but the complex mechanisms underlying its regulation are not completely understood. Here, we show that the eukaryotic translation initiation complex, eIF4F, which binds the 5' cap of mRNAs, regulates the surface expression of interferon-gamma-induced PD-L1 on cancer cells by regulating translation of the mRNA encoding the signal transducer and activator of transcription 1 (STAT1) transcription factor. eIF4F complex formation correlates with response to immunotherapy in human melanoma. Pharmacological inhibition of eIF4A, the RNA helicase component of eIF4F, elicits powerful antitumor immune-mediated effects via PD-L1 downregulation. Thus, eIF4A inhibitors, in development as anticancer drugs, may also act as cancer immunotherapies.