{"doi":"10.1101/2023.02.07.527459","title":"Transient EZH2 suppression by Tazemetostat during <i>in vitro</i> expansion maintains T cell stemness and improves adoptive T cell therapy","abstract":"Abstract The histone methyltransferase enhancer of zeste homolog 2 (EZH2)-mediated epigenetic regulation of T cell differentiation in acute infection has been extensively investigated. However, the role of EZH2 in T cell exhaustion remains under-explored. Here, using in vitro exhaustion models, we demonstrated that transient inhibition of EZH2 in T cells before the phenotypic onset of exhaustion with a clinically approved inhibitor, Tazemetastat, delayed their dysfunctional progression and maintained T cell stemness and polyfunctionality while having no negative impact on cell proliferation. Tazemetestat induced T cell epigenetic reprogramming and increased the expression of the self-renewing T cell transcription factor TCF1 by reducing its promoter H3K27 methylation preferentially in rapidly dividing T cells. In a murine melanoma model, T cells pre-treated with tazemetastat exhibited a superior response to anti-PD-1 blockade therapy after adoptive transfer. Collectively, these data unveil the potential of transient epigenetic reprogramming as a potential intervention to be combined with checkpoint blockade for immune therapy.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":392172,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9483,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":731300,"name":"Jaroslav Žák","orcid":"0000-0002-8135-856X","position":1,"is_corresponding":false},{"id":262638,"name":"Yujie Shi","orcid":"0000-0002-7610-0433","position":2,"is_corresponding":false},{"id":884537,"name":"Isaraphorn Pratumchai","orcid":"0000-0002-3781-242X","position":3,"is_corresponding":false},{"id":1007524,"name":"Brandon Dinner","orcid":"0000-0003-3340-8347","position":4,"is_corresponding":false},{"id":1165421,"name":"Wenjian Wang","orcid":"0000-0001-8690-5895","position":5,"is_corresponding":false},{"id":1033014,"name":"Ke Qin","orcid":"0000-0001-7298-7826","position":6,"is_corresponding":false},{"id":225341,"name":"Evan W. Weber","orcid":"0000-0001-5039-2899","position":7,"is_corresponding":false},{"id":262640,"name":"John R. Teijaro","orcid":"0000-0001-8280-8887","position":8,"is_corresponding":false},{"id":262641,"name":"Peng Wu","orcid":"0000-0002-5204-0229","position":9,"is_corresponding":false},{"id":1165420,"name":"Yingqin Hou","orcid":"0000-0002-0330-040X","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-19T01:18:52.232318Z","pmid":"36798389","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":[]}