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Translational control of tumor immune escape via the eIF4F-STAT1-PD-L1 axis in melanoma.
Nature Medicine ( IF 82.9 ) Pub Date : 2018-Dec-01 , DOI: 10.1038/s41591-018-0217-1 Michaël Cerezo , Ramdane Guemiri , Sabine Druillennec , Isabelle Girault , Hélène Malka-Mahieu , Shensi Shen , Delphine Allard , Sylvain Martineau , Caroline Welsch , Sandrine Agoussi , Charlène Estrada , Julien Adam , Cristina Libenciuc , Emilie Routier , Séverine Roy , Laurent Désaubry , Alexander M. Eggermont , Nahum Sonenberg , Jean Yves Scoazec , Alain Eychène , Stéphan Vagner , Caroline Robert
Nature Medicine ( IF 82.9 ) Pub Date : 2018-Dec-01 , DOI: 10.1038/s41591-018-0217-1 Michaël Cerezo , Ramdane Guemiri , Sabine Druillennec , Isabelle Girault , Hélène Malka-Mahieu , Shensi Shen , Delphine Allard , Sylvain Martineau , Caroline Welsch , Sandrine Agoussi , Charlène Estrada , Julien Adam , Cristina Libenciuc , Emilie Routier , Séverine Roy , Laurent Désaubry , Alexander M. Eggermont , Nahum Sonenberg , Jean Yves Scoazec , Alain Eychène , Stéphan Vagner , Caroline Robert
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-γ-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.
中文翻译:
黑色素瘤中通过eIF4F-STAT1-PD-L1轴进行的肿瘤免疫逃逸的翻译控制。
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有效的抗癌方法。但是,许多患者对检查站封锁没有反应。肿瘤PD-L1表达是一种潜在的功效生物标志物,但尚未完全理解其调控的复杂机制。在这里,我们显示了真核翻译起始复合物eIF4F,它结合mRNA的5'帽,通过调节编码信号转导和激活子的mRNA的翻译来调节干扰素-γ诱导的PD-L1在癌细胞上的表面表达。 1(STAT1)转录因子的表达。eIF4F复合物的形成与人类黑色素瘤对免疫治疗的反应有关。eIF4A(eIF4F的RNA解旋酶成分)的药理抑制作用通过PD-L1下调引起强大的抗肿瘤免疫介导作用。因此,作为抗癌药物开发的eIF4A抑制剂也可以作为癌症免疫疗法。
更新日期:2018-10-30
中文翻译:
黑色素瘤中通过eIF4F-STAT1-PD-L1轴进行的肿瘤免疫逃逸的翻译控制。
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有效的抗癌方法。但是,许多患者对检查站封锁没有反应。肿瘤PD-L1表达是一种潜在的功效生物标志物,但尚未完全理解其调控的复杂机制。在这里,我们显示了真核翻译起始复合物eIF4F,它结合mRNA的5'帽,通过调节编码信号转导和激活子的mRNA的翻译来调节干扰素-γ诱导的PD-L1在癌细胞上的表面表达。 1(STAT1)转录因子的表达。eIF4F复合物的形成与人类黑色素瘤对免疫治疗的反应有关。eIF4A(eIF4F的RNA解旋酶成分)的药理抑制作用通过PD-L1下调引起强大的抗肿瘤免疫介导作用。因此,作为抗癌药物开发的eIF4A抑制剂也可以作为癌症免疫疗法。