Genome-wide CRISPR screens of T cell exhaustion identify chromatin remodeling factors that limit T cell persistence

Julia A. Belk, Winnie Yao, Nghi Ly, Katherine A. Freitas, Yan Ting Chen, Quanming Shi, Alfredo M. Valencia, Eric Shifrut, Nupura Kale, Kathryn E. Yost, Connor V. Duffy, Bence Daniel, Madeline A. Hwee, Zhuang Miao, Alan Ashworth, Crystal L. Mackall, Alexander Marson, Julia Carnevale, Santosh A. Vardhana, Ansuman T. Satpathy*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)768-786.e7
JournalCancer Cell
Issue number7
StatePublished - 11 Jul 2022
Externally publishedYes


  • T cell exhaustion
  • canonical BAF complex
  • chromatin remodeling
  • epigenetics
  • genomics
  • immunology
  • in vivo Perturb-seq


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