The DOI matches its Crossref record; 68 of the 68 references it cites were found in a registry or an index.
Acetylation-dependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy
Open accessAbstract
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. 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.
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Self-citationInterplay between protein acetylation and ubiquitination controls MCL1 protein stability
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Metadata
- Authors
- Gao, Y., Nihira, N. T., Bu, X., Chu, C., Zhang, J., Kolodziejczyk, A., Fan, Y., Chan, N. T., Ma, L., Liu, J., Wang, D., Dai, X., Liu, H., Ono, M., Nakanishi, A., Inuzuka, H., North, B. J., Huang, Y.-H., Sharma, S., Geng, Y., Xu, W., Liu, X. S., Li, L., Miki, Y., Sicinski, P., Freeman, G. J., & Wei, W.
- Venue
- Nature Cell Biology
- Published
- 2020-08-24
- Volume
- 22
- Issue
- 9
- Pages
- 1064-1075
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W3080682266
- Cited by
- 386
- References
- 68
- FWCI
- 13.95
- Type
- journal article
- Language
- en
- Open access
- green
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- Gao, Y., Nihira, N. T., Bu, X., Chu, C., Zhang, J., Kolodziejczyk, A., Fan, Y., Chan, N. T., Ma, L., Liu, J., Wang, D., Dai, X., Liu, H., Ono, M., Nakanishi, A., Inuzuka, H., North, B. J., Huang, Y.-H., Sharma, S., . . . Wei, W. (2020). Acetylation-dependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy. Nature Cell Biology. https://doi.org/10.1038/s41556-020-0562-4
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