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Updated: Aug 6, 2025
Chromatin Immunoprecipitation ChIP in Mouse T-cell Lines
Published on: June 17, 2017
Stepwise activities of mSWI/SNF family chromatin remodeling complexes direct T cell activation and exhaustion
Elena Battistello1, Kimberlee A Hixon2, Dawn E Comstock3
1Department of Pathology and Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA.
Abstract:
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.
Insights
Chromatin remodeling complexes called mSWI/SNF regulate T cell activation and exhaustion. Inhibiting these complexes enhances T cell persistence and memory, improving immunotherapy outcomes.
Area of Science:
- Immunology
- Molecular Biology
- Chromatin Biology
Background:
- T cell activation and exhaustion involve complex gene expression changes.
- Mechanisms regulating these processes and therapeutic targeting are not fully understood.
Purpose of the Study:
- To investigate the role of mSWI/SNF chromatin remodeling complexes in T cell activation and exhaustion.
- To explore therapeutic strategies targeting mSWI/SNF for improved immunotherapy.
Main Methods:
- Comprehensive profiling of mSWI/SNF genomic occupancy during T cell stimulation.
- Genetic and chemical perturbation of mSWI/SNF complexes.
- In vitro and in vivo assessment of T cell phenotypes and anti-tumor activity.
Main Results:
- Stepwise mSWI/SNF localization directs chromatin accessibility and gene activation, leading to distinct T cell phenotypes.
- mSWI/SNF perturbation enhances T cell persistence and memory features.
- Pharmacologic mSWI/SNF inhibition improves CAR-T cell expansion and anti-tumor control.
Conclusions:
- mSWI/SNF complexes are central to coordinating T cell activation and exhaustion.
- Small-molecule inhibition of mSWI/SNF represents a promising strategy to enhance immunotherapy.
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