Stepwise activities of mSWI/SNF family chromatin remodeling complexes direct T cell activation and exhaustion
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved..
Highly coordinated changes in gene expression underlie T cell activation and exhaustion. However, the mechanisms by which such programs are regulated and how these may be targeted for therapeutic benefit remain poorly understood. Here, we comprehensively profile the genomic occupancy of mSWI/SNF chromatin remodeling complexes throughout acute and chronic T cell stimulation, finding that stepwise changes in localization over transcription factor binding sites direct site-specific chromatin accessibility and gene activation leading to distinct phenotypes. Notably, perturbation of mSWI/SNF complexes using genetic and clinically relevant chemical strategies enhances the persistence of T cells with attenuated exhaustion hallmarks and increased memory features in vitro and in vivo. Finally, pharmacologic mSWI/SNF inhibition improves CAR-T expansion and results in improved anti-tumor control in vivo. These findings reveal the central role of mSWI/SNF complexes in the coordination of T cell activation and exhaustion and nominate small-molecule-based strategies for the improvement of current immunotherapy protocols.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:83 |
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| Enthalten in: |
Molecular cell - 83(2023), 8 vom: 20. Apr., Seite 1216-1236.e12 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Battistello, Elena [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 25.04.2023 Date Revised 31.01.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.molcel.2023.02.026 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Highly coordinated changes in gene expression underlie T cell activation and exhaustion. However, the mechanisms by which such programs are regulated and how these may be targeted for therapeutic benefit remain poorly understood. Here, we comprehensively profile the genomic occupancy of mSWI/SNF chromatin remodeling complexes throughout acute and chronic T cell stimulation, finding that stepwise changes in localization over transcription factor binding sites direct site-specific chromatin accessibility and gene activation leading to distinct phenotypes. Notably, perturbation of mSWI/SNF complexes using genetic and clinically relevant chemical strategies enhances the persistence of T cells with attenuated exhaustion hallmarks and increased memory features in vitro and in vivo. Finally, pharmacologic mSWI/SNF inhibition improves CAR-T expansion and results in improved anti-tumor control in vivo. These findings reveal the central role of mSWI/SNF complexes in the coordination of T cell activation and exhaustion and nominate small-molecule-based strategies for the improvement of current immunotherapy protocols | ||
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| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 650 | 4 | |a CRISPR screening | |
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| 700 | 1 | |a Hixon, Kimberlee A |e verfasserin |4 aut | |
| 700 | 1 | |a Comstock, Dawn E |e verfasserin |4 aut | |
| 700 | 1 | |a Collings, Clayton K |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Xufeng |e verfasserin |4 aut | |
| 700 | 1 | |a Rodriguez Hernaez, Javier |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Soobeom |e verfasserin |4 aut | |
| 700 | 1 | |a Cervantes, Kasey S |e verfasserin |4 aut | |
| 700 | 1 | |a Hinkley, Madeline M |e verfasserin |4 aut | |
| 700 | 1 | |a Ntatsoulis, Konstantinos |e verfasserin |4 aut | |
| 700 | 1 | |a Cesarano, Annamaria |e verfasserin |4 aut | |
| 700 | 1 | |a Hockemeyer, Kathryn |e verfasserin |4 aut | |
| 700 | 1 | |a Haining, W Nicholas |e verfasserin |4 aut | |
| 700 | 1 | |a Witkowski, Matthew T |e verfasserin |4 aut | |
| 700 | 1 | |a Qi, Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Tsirigos, Aristotelis |e verfasserin |4 aut | |
| 700 | 1 | |a Perna, Fabiana |e verfasserin |4 aut | |
| 700 | 1 | |a Aifantis, Iannis |e verfasserin |4 aut | |
| 700 | 1 | |a Kadoch, Cigall |e verfasserin |4 aut | |
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