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Published on: March 31, 2019
Genome-wide CRISPR screens of T cell exhaustion identify chromatin remodeling factors that limit T cell persistence
Julia A Belk1, Winnie Yao2, Nghi Ly2
1Department of Computer Science, Stanford University, Stanford, CA 94305, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA.
Abstract:
T cell exhaustion limits antitumor immunity, but the molecular determinants of this process remain poorly understood. Using a chronic stimulation assay, we performed genome-wide CRISPR-Cas9 screens to systematically discover regulators of T cell exhaustion, which identified an enrichment of epigenetic factors. In vivo CRISPR screens in murine and human tumor models demonstrated that perturbation of the INO80 and BAF chromatin remodeling complexes improved T cell persistence in tumors. In vivo Perturb-seq revealed distinct transcriptional roles of each complex and that depletion of canonical BAF complex members, including Arid1a, resulted in the maintenance of an effector program and downregulation of exhaustion-related genes in tumor-infiltrating T cells. Finally, Arid1a depletion limited the acquisition of exhaustion-associated chromatin accessibility and led to improved antitumor immunity. In summary, we provide an atlas of the genetic regulators of T cell exhaustion and demonstrate that modulation of epigenetic state can improve T cell responses in cancer immunotherapy.
Insights
T cell exhaustion hinders cancer immunity. Epigenetic regulators, like the BAF complex member Arid1a, were identified to improve T cell persistence and antitumor responses in tumors.
Area of Science:
- Immunology
- Epigenetics
- Cancer Biology
Background:
- T cell exhaustion is a critical barrier to effective antitumor immunity in cancer.
- The molecular mechanisms driving T cell exhaustion are not fully understood, limiting therapeutic strategies.
Purpose of the Study:
- To systematically identify genetic regulators of T cell exhaustion using genome-wide CRISPR screens.
- To investigate the role of chromatin remodeling complexes in T cell exhaustion and antitumor immunity.
Main Methods:
- Genome-wide CRISPR-Cas9 screens in chronic stimulation assays and in vivo tumor models (murine and human).
- Perturb-seq analysis to determine transcriptional roles of chromatin remodeling complexes.
- Assessment of T cell persistence, effector programs, exhaustion-related gene expression, and chromatin accessibility.
Main Results:
- Epigenetic factors, including the INO80 and BAF chromatin remodeling complexes, were identified as key regulators of T cell exhaustion.
- Perturbation of INO80 and BAF complexes enhanced T cell persistence within tumors.
- Depletion of BAF complex members, such as Arid1a, maintained T cell effector programs, downregulated exhaustion markers, and improved antitumor immunity by limiting epigenetic changes associated with exhaustion.
Conclusions:
- This study provides a comprehensive genetic atlas of T cell exhaustion regulators.
- Targeting epigenetic modifiers, specifically the BAF complex, represents a promising strategy to enhance T cell function in cancer immunotherapy.
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