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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...

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Detalles Bibliográficos
Autores principales: Liu, Yi, Debo, Brian, Li, Mingfeng, Shi, Zhennan, Sheng, Wanqiang, Shi, Yang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
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.
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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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