Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Nature cell biology, 2020-09, Vol.22 (9), p.1064-1075

Ort / Verlag

England

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.