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PD-L1 methylation restricts PD-L1/PD-1 interactions to control cancer immune surveillance
Science Advances ( IF 13.6 ) Pub Date : 2023-05-26 , DOI: 10.1126/sciadv.ade4186 Changsheng Huang 1 , Shengxiang Ren 2 , Yaqi Chen 1 , Anyi Liu 1 , Qi Wu 1 , Tao Jiang 2 , Panjing Lv 3 , Da Song 1 , Fuqing Hu 1 , Jingqing Lan 1 , Li Sun 4 , Xue Zheng 5 , Xuelai Luo 1 , Qian Chu 4 , Keyi Jia 2 , Yan Li 3 , Jun Wang 6 , Caicun Zou 2 , Junbo Hu 1 , Guihua Wang 1
Science Advances ( IF 13.6 ) Pub Date : 2023-05-26 , DOI: 10.1126/sciadv.ade4186 Changsheng Huang 1 , Shengxiang Ren 2 , Yaqi Chen 1 , Anyi Liu 1 , Qi Wu 1 , Tao Jiang 2 , Panjing Lv 3 , Da Song 1 , Fuqing Hu 1 , Jingqing Lan 1 , Li Sun 4 , Xue Zheng 5 , Xuelai Luo 1 , Qian Chu 4 , Keyi Jia 2 , Yan Li 3 , Jun Wang 6 , Caicun Zou 2 , Junbo Hu 1 , Guihua Wang 1
Affiliation
Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) or programmed cell death 1 ligand 1 (PD-L1) have enabled some patients with cancer to experience durable, complete treatment responses; however, reliable anti–PD-(L)1 treatment response biomarkers are lacking. Our research found that PD-L1 K162 was methylated by SETD7 and demethylated by LSD2. Furthermore, PD-L1 K162 methylation controlled the PD-1/PD-L1 interaction and obviously enhanced the suppression of T cell activity controlling cancer immune surveillance. We demonstrated that PD-L1 hypermethylation was the key mechanism for anti–PD-L1 therapy resistance, investigated that PD-L1 K162 methylation was a negative predictive marker for anti–PD-1 treatment in patients with non–small cell lung cancer, and showed that the PD-L1 K162 methylation:PD-L1 ratio was a more accurate biomarker for predicting anti–PD-(L)1 therapy sensitivity. These findings provide insights into the regulation of the PD-1/PD-L1 pathway, identify a modification of this critical immune checkpoint, and highlight a predictive biomarker of the response to PD-1/PD-L1 blockade therapy.
中文翻译:
PD-L1 甲基化限制 PD-L1/PD-1 相互作用以控制癌症免疫监视
针对程序性细胞死亡蛋白 1 (PD-1) 或程序性细胞死亡 1 配体 1 (PD-L1) 的免疫检查点抑制剂已使一些癌症患者获得持久、完整的治疗反应;然而,缺乏可靠的抗 PD-(L)1 治疗反应生物标志物。我们的研究发现 PD-L1 K162 被 SETD7 甲基化并被 LSD2 去甲基化。此外,PD-L1 K162 甲基化控制 PD-1/PD-L1 相互作用并显着增强对控制癌症免疫监视的 T 细胞活性的抑制。我们证明了 PD-L1 高甲基化是抗 PD-L1 治疗耐药的关键机制,研究了 PD-L1 K162 甲基化是非小细胞肺癌患者抗 PD-1 治疗的阴性预测标志物,并且显示 PD-L1 K162 甲基化:PD-L1 比率是预测抗 PD-(L)1 治疗敏感性的更准确的生物标志物。这些发现提供了对 PD-1/PD-L1 通路调控的见解,确定了这一关键免疫检查点的修饰,并突出了对 PD-1/PD-L1 阻断疗法反应的预测性生物标志物。
更新日期:2023-05-26
中文翻译:
PD-L1 甲基化限制 PD-L1/PD-1 相互作用以控制癌症免疫监视
针对程序性细胞死亡蛋白 1 (PD-1) 或程序性细胞死亡 1 配体 1 (PD-L1) 的免疫检查点抑制剂已使一些癌症患者获得持久、完整的治疗反应;然而,缺乏可靠的抗 PD-(L)1 治疗反应生物标志物。我们的研究发现 PD-L1 K162 被 SETD7 甲基化并被 LSD2 去甲基化。此外,PD-L1 K162 甲基化控制 PD-1/PD-L1 相互作用并显着增强对控制癌症免疫监视的 T 细胞活性的抑制。我们证明了 PD-L1 高甲基化是抗 PD-L1 治疗耐药的关键机制,研究了 PD-L1 K162 甲基化是非小细胞肺癌患者抗 PD-1 治疗的阴性预测标志物,并且显示 PD-L1 K162 甲基化:PD-L1 比率是预测抗 PD-(L)1 治疗敏感性的更准确的生物标志物。这些发现提供了对 PD-1/PD-L1 通路调控的见解,确定了这一关键免疫检查点的修饰,并突出了对 PD-1/PD-L1 阻断疗法反应的预测性生物标志物。