{"doi":"10.1101/2022.04.20.488974","title":"Genome-wide CRISPR screens of T cell exhaustion identify chromatin remodeling factors that limit T cell persistence","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  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.\n                  <jats:italic>In vivo</jats:italic>\n                  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.\n                  <jats:italic>In vivo</jats:italic>\n                  paired CRISPR perturbation and single-cell RNA sequencing revealed distinct transcriptional roles of each complex and that depletion of canonical BAF complex members, including\n                  <jats:italic>Arid1a</jats:italic>\n                  , resulted in the maintenance of an effector program and downregulation of terminal exhaustion-related genes in tumor-infiltrating T cells. Finally,\n                  <jats:italic>Arid1a</jats:italic>\n                  -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.\n                </jats:p>","journal":null,"year":null,"id":641232,"datarank":0.5416376868966337,"base_score":3.6109179126442243,"endowment":3.6109179126442243,"self_citation_contribution":0.5416376868966337,"citation_network_contribution":0.0,"self_endowment_contribution":0.5416376868966337,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":36,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":839822,"name":"Winnie Yao","orcid":"0000-0003-1159-5153","position":1,"is_corresponding":false},{"id":700161,"name":"Nghi Ly","orcid":null,"position":2,"is_corresponding":false},{"id":640061,"name":"Katherine A. Freitas","orcid":"0000-0001-9480-7320","position":3,"is_corresponding":false},{"id":1667006,"name":"Yan-Ting Chen","orcid":null,"position":4,"is_corresponding":false},{"id":291362,"name":"Quanming Shi","orcid":"0000-0003-2109-5048","position":5,"is_corresponding":false},{"id":246356,"name":"Alfredo M. Valencia","orcid":"0000-0003-2432-9890","position":6,"is_corresponding":false},{"id":240952,"name":"Eric Shifrut","orcid":"0000-0001-6827-0128","position":7,"is_corresponding":false},{"id":636378,"name":"Nupura Kale","orcid":"0000-0002-3185-8646","position":8,"is_corresponding":false},{"id":227860,"name":"Kathryn E. Yost","orcid":"0000-0001-6807-950X","position":9,"is_corresponding":false},{"id":555972,"name":"Connor V. Duffy","orcid":"0000-0002-3974-5654","position":10,"is_corresponding":false},{"id":617158,"name":"Madeline A. Hwee","orcid":null,"position":11,"is_corresponding":false},{"id":743411,"name":"Zhuang Miao","orcid":"0000-0003-2289-4589","position":12,"is_corresponding":false},{"id":7895,"name":"Alan Ashworth","orcid":"0000-0003-1446-7878","position":13,"is_corresponding":false},{"id":225351,"name":"Crystal L. Mackall","orcid":"0000-0003-0359-9023","position":14,"is_corresponding":false},{"id":563050,"name":"Alexander Marson","orcid":"0000-0002-2760-2154","position":15,"is_corresponding":false},{"id":625671,"name":"Julia Carnevale","orcid":"0000-0001-9410-7148","position":16,"is_corresponding":false},{"id":1667007,"name":"Santosh A. Vardhana","orcid":null,"position":17,"is_corresponding":false},{"id":21653,"name":"Ansuman T. Satpathy","orcid":"0000-0002-5167-537X","position":18,"is_corresponding":false},{"id":262617,"name":"Julia A. Belk","orcid":"0000-0003-4724-6158","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-08-07T16:45:50.736240Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}