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LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade
Exhausted CD8(+) T cells are key targets of immune checkpoint blockade therapy and their ineffective reinvigoration limits the durable benefit in some cancer patients. Here, we demonstrate that histone demethylase LSD1 acts to enforce an epigenetic program in progenitor exhausted CD8(+) T cells to a...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8613218/ https://www.ncbi.nlm.nih.gov/pubmed/34819502 http://dx.doi.org/10.1038/s41467-021-27179-7 |
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author | Liu, Yi Debo, Brian Li, Mingfeng Shi, Zhennan Sheng, Wanqiang Shi, Yang |
author_facet | Liu, Yi Debo, Brian Li, Mingfeng Shi, Zhennan Sheng, Wanqiang Shi, Yang |
author_sort | Liu, Yi |
collection | PubMed |
description | Exhausted CD8(+) T cells are key targets of immune checkpoint blockade therapy and their ineffective reinvigoration limits the durable benefit in some cancer patients. Here, we demonstrate that histone demethylase LSD1 acts to enforce an epigenetic program in progenitor exhausted CD8(+) T cells to antagonize the TCF1-mediated progenitor maintenance and to promote terminal differentiation. Consequently, genetic perturbation or small molecules targeting LSD1 increases the persistence of the progenitor exhausted CD8(+) T cells, which provide a sustained source for the proliferative conversion to numerically larger terminally exhausted T cells with tumor-killing cytotoxicity, thereby leading to effective and durable responses to anti-PD1 therapy. Collectively, our findings provide important insights into epigenetic mechanisms that regulate T cell exhaustion and have important implications for durable immunotherapy. |
format | Online Article Text |
id | pubmed-8613218 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-86132182021-12-01 LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade Liu, Yi Debo, Brian Li, Mingfeng Shi, Zhennan Sheng, Wanqiang Shi, Yang Nat Commun Article Exhausted CD8(+) T cells are key targets of immune checkpoint blockade therapy and their ineffective reinvigoration limits the durable benefit in some cancer patients. Here, we demonstrate that histone demethylase LSD1 acts to enforce an epigenetic program in progenitor exhausted CD8(+) T cells to antagonize the TCF1-mediated progenitor maintenance and to promote terminal differentiation. Consequently, genetic perturbation or small molecules targeting LSD1 increases the persistence of the progenitor exhausted CD8(+) T cells, which provide a sustained source for the proliferative conversion to numerically larger terminally exhausted T cells with tumor-killing cytotoxicity, thereby leading to effective and durable responses to anti-PD1 therapy. Collectively, our findings provide important insights into epigenetic mechanisms that regulate T cell exhaustion and have important implications for durable immunotherapy. Nature Publishing Group UK 2021-11-24 /pmc/articles/PMC8613218/ /pubmed/34819502 http://dx.doi.org/10.1038/s41467-021-27179-7 Text en © The Author(s) 2021, corrected publication 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Liu, Yi Debo, Brian Li, Mingfeng Shi, Zhennan Sheng, Wanqiang Shi, Yang LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade |
title | LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade |
title_full | LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade |
title_fullStr | LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade |
title_full_unstemmed | LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade |
title_short | LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade |
title_sort | lsd1 inhibition sustains t cell invigoration with a durable response to pd-1 blockade |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8613218/ https://www.ncbi.nlm.nih.gov/pubmed/34819502 http://dx.doi.org/10.1038/s41467-021-27179-7 |
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