@article{4f97847cbcd843fcac18b1f6854fdab6,
title = "Acetylation-dependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy",
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.",
author = "Yang Gao and Nihira, {Naoe Taira} and Xia Bu and Chen Chu and Jinfang Zhang and Aleksandra Kolodziejczyk and Yizeng Fan and Chan, {Ngai Ting} and Leina Ma and Jing Liu and Dong Wang and Xiaoming Dai and Huadong Liu and Masaya Ono and Akira Nakanishi and Hiroyuki Inuzuka and North, {Brian J.} and Huang, {Yu Han} and Samanta Sharma and Yan Geng and Wei Xu and Liu, {X. Shirley} and Lei Li and Yoshio Miki and Piotr Sicinski and Freeman, {Gordon J.} and Wenyi Wei",
note = "Funding Information: We thank J. Guo, F. Dang and other members of the Wei laboratory for reading the manuscript, as well as members of the Wei, Freeman and Sicinski laboratories for helpful discussions. We thank staff at the Microscopy Resources on the North Quad (MicRoN) core at Harvard Medical School for helping with IF experiments. This research was supported in part by the NIH grants (R01CA177910 and R01GM094777, to W.W.; P50CA101942, to G.J.F.; R01CA236226 and R01CA202634, to P.S.; and R01CA236356, to W.X.); the Japan Society for Promotion of Science (JSPS) KAKENHI Grant (JP18H06157, to N.T.N). N.T.N. is supported by JSPS Research Fellowships for Young Scientists and the Osamu Hayaishi Memorial Scholarship for Study Abroad. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2020",
month = sep,
day = "1",
doi = "10.1038/s41556-020-0562-4",
language = "English",
volume = "22",
pages = "1064--1075",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "9",
}