Acetylation-dependent Regulation of PD-L1 Nuclear Translocation Dictates the Efficacy of Anti-PD-1 Immunotherapy

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2020 Aug 26

PMID 32839551

Citations 177

Authors

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 Geng

Wei Xu

X Shirley Liu

Lei Li

Yoshio Miki

Piotr Sicinski

Gordon J Freeman

Wenyi Wei

Affiliations

Soon will be listed here.

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.

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