免疫检查点程序性细胞死亡蛋白配体-1翻译后修饰及其在免疫治疗中的应用前景

Posttranslational Modifications of PD-L1 and Its Prospect Application in Immunotherapy

免疫检查点程序性细胞死亡蛋白配体-1(programmed cell death 1 ligand 1,PD-L1)是一种主要表达于肿瘤细胞表面的免疫抑制性分子,其可与T淋巴细胞表面的程序性细胞死亡蛋白-1(programmed cell death protein 1,PD-1)结合,抑制T淋巴细胞的激活,发挥免疫抑制性功能。基于这一原理所开发的PD-1/PD-L1免疫阻断疗法,已在临床广泛应用于多种实体瘤的治疗,使诸多病人受益。与此同时,随着对PD-L1调控机制研究的深入,PD-L1的多种翻译后修饰形式陆续得到了鉴定,包括糖基化、磷酸化、泛素化和棕榈酰化等。研究表明,这些翻译后修饰过程可影响PD-L1的蛋白质稳定性与生理功能。因此,翻译后修饰成了PD-L1研究新的切入点。目前,PD-L1翻译后修饰靶向药物已在免疫治疗中展现出良好的应用前景。通过靶向PD-L1翻译后修饰过程,进而调控由PD-L1介导的肿瘤免疫逃逸,成了提高免疫治疗应答率的新思路和新策略。本文将对PD-L1翻译后修饰的研究进行系统总结,并陈述其在免疫治疗领域中的应用前景,希望为未来针对PD-L1翻译后修饰的研究提供理论支持。

PD-L1(programmed cell death 1 ligand 1)is an immunosuppressive ligand which mainly expressed on tumor cells,inhibiting the activation of T lymphocytes through binding with PD-1(programmed cell death protein 1),thus leading to immune escape.PD-1/PD-L1 immune checkpoint blockade therapy,which established based on the above mechanism,gained success in the clinical treatment of solid tumors.Various kinds of PD-L1 posttranslational modifications were identified following the in-depth studies of PD-L1,including glycosylation,phosphorylation,ubiquitination,palmitoylation,et al.Meanwhile,multiple studies indicated that posttranslational modifications governs PD-L1-mediated immune escape through regulating the protein stability and physiological functions of PD-L1,which makes posttranslational modifications of PD-L1 turns into a new"entry"point of PD-L1 studies.Drugs targeting posttranslational modifications of PD-L1 exhibited favorable applicational prospects in immunotherapy at the same time.Regulating PD-L1-mediated immune escape through intervening PD-L1 posttranslational modifications becomes a new strategy for improving the efficacy of immunotherapy.In this review,we summarized the posttranslational modifications of PD-L1 and its applicational prospects in immunotherapy,hoping to provide theoretical supports for future studies focused on PD-L1.