Acetylation-dependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy

• Published in: Nature cell biology Vol. 22; no. 9; pp. 1064 - 1075
• Main Authors: Gao, Yang, Nihira, Naoe Taira, Bu, Xia, Chu, Chen, Zhang, Jinfang, Kolodziejczyk, Aleksandra, Fan, Yizeng, Chan, Ngai Ting, Ma, Leina, Liu, Jing, Wang, Dong, Dai, Xiaoming, Liu, Huadong, Ono, Masaya, Nakanishi, Akira, Inuzuka, Hiroyuki, North, Brian J., Huang, Yu-Han, Sharma, Samanta, Geng, Yan, Xu, Wei, Liu, X. Shirley, Li, Lei, Miki, Yoshio, Sicinski, Piotr, Freeman, Gordon J., Wei, Wenyi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2020; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/109; 13/31; 13/95; 14/19; 38/23; 38/91; 631/250/580; 631/67/1059/2325; 631/80/458/1275; 692/699/67; 82; 82/58; 82/83; 96; Acetylation; Animals; Apoptosis; B7-H1 Antigen - metabolism; Biomedical and Life Sciences; Cancer Research; Cell Biology; Cell death; Cell Line; Cell Line, Tumor; Cell Nucleus - metabolism; Cellular proteins; CTLA-4 protein; Cytotoxicity; Deacetylation; Developmental Biology; E1A-Associated p300 Protein - metabolism; Endocytosis; Gene expression; Gene Expression - physiology; Genes; HDAC2 protein; Health aspects; HEK293 Cells; Histone deacetylase; Humans; Immune checkpoint; Immune system; Immunotherapy; Immunotherapy - methods; Life Sciences; Localization; Lymphocytes; Lymphocytes T; MCF-7 Cells; Medical research; Medicine, Experimental; Mice; Neoplasms - metabolism; Nuclear transport; PD-1 protein; PD-L1 protein; Programmed Cell Death 1 Receptor - metabolism; Protein Processing, Post-Translational - physiology; Proteins; RAW 264.7 Cells; Stem Cells; Translocation; Translocation (Genetics); Tumors; United States
• ISSN: 1465-7392; 1476-4679; 1476-4679
• DOI: 10.1038/s41556-020-0562-4

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. Gao et al. uncover p300-induced acetylation and HDAC2-mediated deacetylation of PD-L1, which modulate its nuclear translocation to affect the expression of immune genes and the efficacy of anti-PD-1 therapy.