{"doi":"10.1016/j.cell.2016.08.052","title":"A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells","abstract":"Reversing the dysfunctional T cell state that arises in cancer and chronic viral infections is the focus of therapeutic interventions; however, current therapies are effective in only some patients and some tumor types. To gain a deeper molecular understanding of the dysfunctional T cell state, we analyzed population and single-cell RNA profiles of CD8(+) tumor-infiltrating lymphocytes (TILs) and used genetic perturbations to identify a distinct gene module for T cell dysfunction that can be uncoupled from T cell activation. This distinct dysfunction module is downstream of intracellular metallothioneins that regulate zinc metabolism and can be identified at single-cell resolution. We further identify Gata-3, a zinc-finger transcription factor in the dysfunctional module, as a regulator of dysfunction, and we use CRISPR-Cas9 genome editing to show that it drives a dysfunctional phenotype in CD8(+) TILs. Our results open novel avenues for targeting dysfunctional T cell states while leaving activation programs intact.","journal":"Cell","year":2016,"id":10532,"datarank":0.9102638382366167,"base_score":6.068425588244111,"endowment":6.068425588244111,"self_citation_contribution":0.9102638382366167,"citation_network_contribution":0.0,"self_endowment_contribution":0.9102638382366167,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":431,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0435,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2016-09-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":6927,"name":"Chao Wang","orcid":"0000-0003-3084-6093","position":1,"is_corresponding":false},{"id":15696,"name":"Le Cong","orcid":"0000-0003-4725-8714","position":2,"is_corresponding":false},{"id":28702,"name":"Nemanja Despot Marjanovic","orcid":null,"position":3,"is_corresponding":false},{"id":2681,"name":"Monika S. Kowalczyk","orcid":"0000-0003-0525-9196","position":4,"is_corresponding":false},{"id":7836,"name":"Huiyuan Zhang","orcid":"0000-0002-1532-2462","position":5,"is_corresponding":false},{"id":14738,"name":"Jackson Nyman","orcid":"0000-0001-6151-6930","position":6,"is_corresponding":false},{"id":58385,"name":"Kaori Sakuishi","orcid":null,"position":7,"is_corresponding":false},{"id":58386,"name":"Sema Kurtulus","orcid":null,"position":8,"is_corresponding":false},{"id":25301,"name":"David Gennert","orcid":"0000-0002-8668-3601","position":9,"is_corresponding":false},{"id":51572,"name":"Junrong Xia","orcid":"0000-0002-2818-1494","position":10,"is_corresponding":false},{"id":50396,"name":"James Nevin","orcid":"0000-0002-8957-7118","position":12,"is_corresponding":false},{"id":17248,"name":"Rebecca H. Herbst","orcid":"0000-0002-1004-8919","position":13,"is_corresponding":false},{"id":58388,"name":"Itai Yanai","orcid":"0000-0002-8438-2741","position":14,"is_corresponding":false},{"id":6940,"name":"Vijay K. Kuchroo","orcid":"0000-0001-7177-2110","position":16,"is_corresponding":false},{"id":29633,"name":"Prisca Liberali","orcid":"0000-0003-0695-6081","position":17,"is_corresponding":false},{"id":3016,"name":"Ana. C. Anderson","orcid":"0000-0002-0877-2932","position":18,"is_corresponding":false},{"id":58389,"name":"Sema Kurtuluş","orcid":"0000-0002-2842-9437","position":19,"is_corresponding":false},{"id":58390,"name":"John Y. H. Kwon","orcid":"0000-0001-5700-238X","position":20,"is_corresponding":false},{"id":2697,"name":"Orit Rozenblatt–Rosen","orcid":"0000-0001-6313-3570","position":21,"is_corresponding":false},{"id":34472,"name":"Meromit Singer","orcid":"0000-0002-1755-3598","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-03-01T18:20:47.508186Z","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":[]}