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Acetylation-dependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy.
Nature Cell Biology ( IF 17.3 ) Pub Date : 2020-08-24 , DOI: 10.1038/s41556-020-0562-4
Yang Gao 1, 2 , Naoe Taira Nihira 1, 3, 4 , Xia Bu 5 , Chen Chu 6, 7 , Jinfang Zhang 1 , Aleksandra Kolodziejczyk 6, 7 , Yizeng Fan 1, 2 , Ngai Ting Chan 8 , Leina Ma 1 , Jing Liu 1 , Dong Wang 1 , Xiaoming Dai 1 , Huadong Liu 9 , Masaya Ono 10 , Akira Nakanishi 3 , Hiroyuki Inuzuka 1 , Brian J North 1 , Yu-Han Huang 11, 12 , Samanta Sharma 6, 7 , Yan Geng 6, 7 , Wei Xu 8 , X Shirley Liu 13 , Lei Li 2 , Yoshio Miki 3 , Piotr Sicinski 6, 7 , Gordon J Freeman 5 , Wenyi Wei 1
Affiliation  

Immunotherapies that target programmed cell death protein 1 (PD-1) and its ligand PD-L1 as well as cytotoxic T-lymphocyte-associated protein 4 (CTLA4) have shown impressive clinical outcomes for multiple tumours. However, only a subset of patients achieves durable responses, suggesting that the mechanisms of the immune checkpoint pathways are not completely understood. Here, we report that PD-L1 translocates from the plasma membrane into the nucleus through interactions with components of the endocytosis and nucleocytoplasmic transport pathways, regulated by p300-mediated acetylation and HDAC2-dependent deacetylation of PD-L1. Moreover, PD-L1 deficiency leads to compromised expression of multiple immune-response-related genes. Genetically or pharmacologically modulating PD-L1 acetylation blocks its nuclear translocation, reprograms the expression of immune-response-related genes and, as a consequence, enhances the anti-tumour response to PD-1 blockade. Thus, our results reveal an acetylation-dependent regulation of PD-L1 nuclear localization that governs immune-response gene expression, and thereby advocate targeting PD-L1 translocation to enhance the efficacy of PD-1/PD-L1 blockade.



中文翻译:


PD-L1 核易位的乙酰化依赖性调节决定了抗 PD-1 免疫疗法的疗效。



针对程序性细胞死亡蛋白 1 (PD-1) 及其配体 PD-L1 以及细胞毒性 T 淋巴细胞相关蛋白 4 (CTLA4) 的免疫疗法在治疗多种肿瘤方面已显示出令人印象深刻的临床效果。然而,只有一小部分患者获得了持久的反应,这表明免疫检查点途径的机制尚未完全了解。在这里,我们报告说,PD-L1 通过与胞吞作用和核质运输途径的成分相互作用,从质膜易位到细胞核中,并受到 p300 介导的 PD-L1 乙酰化和 HDAC2 依赖性脱乙酰化的调节。此外,PD-L1 缺陷会导致多个免疫反应相关基因的表达受损。通过基因或药理学调节 PD-L1 乙酰化可阻断其核转位,重新编程免疫反应相关基因的表达,从而增强对 PD-1 阻断的抗肿瘤反应。因此,我们的结果揭示了 PD-L1 核定位的乙酰化依赖性调节,控制着免疫反应基因的表达,从而主张靶向 PD-L1 易位以增强 PD-1/PD-L1 阻断的功效。

更新日期:2020-08-24
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