{"doi":"10.1016/j.medj.2022.07.008","title":"Internal checkpoint regulates T cell neoantigen reactivity and susceptibility to PD1 blockade","abstract":"BACKGROUND: Adoptive transfer of tumor-infiltrating lymphocytes (TIL) fails to consistently elicit tumor rejection. Manipulation of intrinsic factors that inhibit T cell effector function and neoantigen recognition may therefore improve TIL therapy outcomes. We previously identified the cytokine-induced SH2 protein (CISH) as a key regulator of T cell functional avidity in mice. Here, we investigate the mechanistic role of CISH in regulating human T cell effector function in solid tumors and demonstrate that CRISPR/Cas9 disruption of CISH enhances TIL neoantigen recognition and response to checkpoint blockade. METHODS: Single-cell gene expression profiling was used to identify a negative correlation between high CISH expression and TIL activation in patient-derived TIL. A GMP-compliant CRISPR/Cas9 gene editing process was developed to assess the impact of CISH disruption on the molecular and functional phenotype of human peripheral blood T cells and TIL. Tumor-specific T cells with disrupted Cish function were adoptively transferred into tumor-bearing mice and evaluated for efficacy with or without checkpoint blockade. FINDINGS: CISH expression was associated with T cell dysfunction. CISH deletion using CRISPR/Cas9 resulted in hyper-activation and improved functional avidity against tumor-derived neoantigens without perturbing T cell maturation. Cish knockout resulted in increased susceptibility to checkpoint blockade in vivo. CONCLUSIONS: CISH negatively regulates human T cell effector function, and its genetic disruption offers a novel avenue to improve the therapeutic efficacy of adoptive TIL therapy. FUNDING: This study was funded by Intima Bioscience, U.S. and in part through the Intramural program CCR at the National Cancer Institute.","journal":"Med","year":2022,"id":235674,"datarank":0.6535063240034389,"base_score":4.356708826689592,"endowment":4.356708826689592,"self_citation_contribution":0.6535063240034389,"citation_network_contribution":0.0,"self_endowment_contribution":0.6535063240034389,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":77,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9539,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":254328,"name":"Beau R. Webber","orcid":"0000-0002-3950-8747","position":1,"is_corresponding":false},{"id":555933,"name":"Yogin Patel","orcid":"0000-0002-1951-009X","position":2,"is_corresponding":false},{"id":6709,"name":"Matthew J. Johnson","orcid":"0000-0002-1313-1742","position":3,"is_corresponding":false},{"id":257259,"name":"Christine M. Kariya","orcid":null,"position":4,"is_corresponding":false},{"id":555934,"name":"Walker S. Lahr","orcid":"0000-0002-3288-3843","position":5,"is_corresponding":false},{"id":226277,"name":"Maria R. Parkhurst","orcid":"0000-0001-7231-5069","position":6,"is_corresponding":false},{"id":226275,"name":"Jared J. Gartner","orcid":"0000-0003-2924-3519","position":7,"is_corresponding":false},{"id":228785,"name":"Todd D. Prickett","orcid":"0000-0001-5466-4150","position":8,"is_corresponding":false},{"id":226265,"name":"Frank J. Lowery","orcid":"0000-0002-4620-5293","position":9,"is_corresponding":false},{"id":255929,"name":"Rigel J. Kishton","orcid":"0000-0002-5682-3896","position":10,"is_corresponding":false},{"id":226272,"name":"Devikala Gurusamy","orcid":"0000-0002-1727-8653","position":11,"is_corresponding":false},{"id":556679,"name":"Zulmarie Franco","orcid":null,"position":12,"is_corresponding":false},{"id":255930,"name":"Suman K. Vodnala","orcid":"0000-0001-6753-5788","position":13,"is_corresponding":false},{"id":556680,"name":"Miechaleen D. Diers","orcid":null,"position":14,"is_corresponding":false},{"id":555935,"name":"Natalie K. Wolf","orcid":"0000-0002-2015-3384","position":15,"is_corresponding":false},{"id":417672,"name":"Nicholas J. Slipek","orcid":"0000-0003-2664-6507","position":16,"is_corresponding":false},{"id":412072,"name":"David H. McKenna","orcid":"0000-0001-8734-0996","position":17,"is_corresponding":false},{"id":556681,"name":"Darin Sumstad","orcid":null,"position":18,"is_corresponding":false},{"id":556682,"name":"Lydia Viney","orcid":null,"position":19,"is_corresponding":false},{"id":556683,"name":"Tom Henley","orcid":null,"position":20,"is_corresponding":false},{"id":555936,"name":"Tilmann Bürckstümmer","orcid":"0000-0001-5681-8045","position":21,"is_corresponding":false},{"id":8102,"name":"O. K. Baker","orcid":"0000-0003-1346-5774","position":22,"is_corresponding":false},{"id":504210,"name":"Ying Hu","orcid":"0000-0002-0794-742X","position":23,"is_corresponding":false},{"id":4142,"name":"Chunhua Yan","orcid":"0000-0001-5474-7431","position":24,"is_corresponding":false},{"id":418276,"name":"Daoud Meerzaman","orcid":"0000-0002-0129-5256","position":25,"is_corresponding":false},{"id":556684,"name":"Kartik Padhan","orcid":null,"position":26,"is_corresponding":false},{"id":556685,"name":"Winnie Lo","orcid":null,"position":27,"is_corresponding":false},{"id":268734,"name":"Parisa Malekzadeh","orcid":"0000-0002-1749-1198","position":28,"is_corresponding":false},{"id":226269,"name":"Li Jia","orcid":"0000-0002-9450-7376","position":29,"is_corresponding":false},{"id":268739,"name":"Drew C. Deniger","orcid":"0000-0002-9299-9688","position":30,"is_corresponding":false},{"id":255934,"name":"Shashank J. Patel","orcid":"0000-0001-6973-6997","position":31,"is_corresponding":false},{"id":226282,"name":"Paul F. Robbins","orcid":"0000-0002-1260-8123","position":32,"is_corresponding":false},{"id":406232,"name":"R. Scott McIvor","orcid":"0000-0001-8726-0902","position":33,"is_corresponding":false},{"id":556686,"name":"Modassir Choudhry","orcid":null,"position":34,"is_corresponding":false},{"id":226283,"name":"Steven A. Rosenberg","orcid":"0000-0002-8939-8910","position":35,"is_corresponding":false},{"id":254329,"name":"Branden S. Moriarity","orcid":"0000-0002-3031-3767","position":36,"is_corresponding":false},{"id":257262,"name":"Nicholas P. Restifo","orcid":null,"position":37,"is_corresponding":false},{"id":255932,"name":"Douglas C. Palmer","orcid":"0000-0001-5018-5734","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:21:53.333008Z","pmid":"36007524","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":[]}