Acetylation-dependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy
- 23 August 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 22 (9), 1064-+
- https://doi.org/10.1038/s41556-020-0562-4
Abstract
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. 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.Keywords
Funding Information
- MEXT | Japan Society for the Promotion of Science (JP18H06157)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (CA236356, CA236226, CA202634, CA101942, CA177910)
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (GM094777)
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