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

Yang Gao, Naoe Taira Nihira, Xia Bu, Chen Chu, Jinfang Zhang, Aleksandra Kolodziejczyk, Yizeng Fan, Ngai Ting Chan, Leina Ma, Jing Liu, Dong Wang, Xiaoming Dai, Huadong Liu, Masaya Ono, Akira Nakanishi, Hiroyuki Inuzuka, Brian J. North, Yu Han Huang, Samanta Sharma, Yan GengWei Xu, X. Shirley Liu, Lei Li, Yoshio Miki, Piotr Sicinski, Gordon J. Freeman, Wenyi Wei

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1064-1075
Number of pages12
JournalNature Cell Biology
Volume22
Issue number9
DOIs
StatePublished - Sep 1 2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Cell Biology

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