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

Authors :
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
Madeline A. Hwee
Zhuang Miao
Alan Ashworth
Crystal L. Mackall
Alexander Marson
Julia Carnevale
Santosh A. Vardhana
Ansuman T. Satpathy
Publication Year :
2022
Publisher :
Cold Spring Harbor Laboratory, 2022.

Abstract

T cell exhaustion limits anti-tumor immunity, but the molecular determinants of this process remain poorly understood. Using a chronic antigen stimulation assay, we performed genome-wide CRISPR/Cas9 screens to systematically discover genetic 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 several epigenetic regulators, including members of the INO80 and BAF chromatin remodeling complexes, improved T cell persistence in tumors. In vivo paired CRISPR perturbation and single-cell RNA sequencing 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 terminal exhaustion-related genes in tumor-infiltrating T cells. Finally, Arid1a-depletion limited the global acquisition of chromatin accessibility associated with T cell exhaustion and led to improved anti-tumor immunity after adoptive cell therapy. In summary, we provide a comprehensive atlas of the genetic regulators of T cell exhaustion and demonstrate that modulation of the epigenetic state of T cell exhaustion can improve T cell responses in cancer immunotherapy.

Details

Database :
OpenAIRE
Accession number :
edsair.doi...........f43c061aa8589a9656067aa9ec535a2a