{"doi":"10.1101/2023.03.14.532663","title":"Immunogenetic metabolomics revealed key enzymes that modulate CAR-T metabolism and function","abstract":"Abstract Immune evasion is a critical step of cancer progression that remains a major obstacle for current T cell-based immunotherapies. Hence, we seek to genetically reprogram T cells to exploit a common tumor-intrinsic evasion mechanism, whereby cancer cells suppress T cell function by generating a metabolically unfavorable tumor microenvironment (TME). Specifically, we use an in silico screen to identify ADA and PDK1 as metabolic regulators, in which gene overexpression (OE) enhances the cytolysis of CD19-specific CD8 CAR-T cells against cognate leukemia cells, and conversely, ADA or PDK1 deficiency dampens such effect. ADA -OE in CAR-T cells improves cancer cytolysis under high concentrations of adenosine, the ADA substrate and an immunosuppressive metabolite in the TME. High-throughput transcriptomics and metabolomics in these CAR-Ts reveal alterations of global gene expression and metabolic signatures in both ADA- and PDK1- engineered CAR-T cells. Functional and immunological analyses demonstrate that ADA -OE increases proliferation and decreases exhaustion in α-CD19 and α-HER2 CAR-T cells. ADA-OE improves tumor infiltration and clearance by α-HER2 CAR-T cells in an in vivo colorectal cancer model. Collectively, these data unveil systematic knowledge of metabolic reprogramming directly in CAR-T cells, and reveal potential targets for improving CAR-T based cell therapy. Synopsis The authors identify the adenosine deaminase gene (ADA) as a regulatory gene that reprograms T cell metabolism. ADA-overexpression (OE) in α-CD19 and α-HER2 CAR-T cells increases proliferation, cytotoxicity, memory, and decreases exhaustion, and ADA-OE α-HER2 CAR-T cells have enhanced clearance of HT29 human colorectal cancer tumors in vivo .","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":398753,"datarank":0.13654403483563432,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.032571957751642504,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.032571957751642504,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":1,"citers_with_citation_signal":1,"citers_with_endowment":1,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9594,"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":246105,"name":"Jonathan J. Park","orcid":"0000-0001-5887-3953","position":1,"is_corresponding":false},{"id":990807,"name":"Meizhu Bai","orcid":"0000-0001-8208-4073","position":2,"is_corresponding":false},{"id":1056024,"name":"Arianny Acosta","orcid":"0009-0008-7208-2419","position":3,"is_corresponding":false},{"id":1033324,"name":"Won‐Ho Lee","orcid":"0009-0000-5158-1202","position":4,"is_corresponding":false},{"id":1056025,"name":"Guang Han Lin","orcid":"0009-0001-1973-5897","position":5,"is_corresponding":false},{"id":365944,"name":"Yueqi Zhang","orcid":"0000-0002-1189-2118","position":6,"is_corresponding":false},{"id":259573,"name":"Xiaoyun Dai","orcid":"0000-0002-6162-5202","position":7,"is_corresponding":false},{"id":259567,"name":"Guangchuan Wang","orcid":"0000-0001-5315-1599","position":8,"is_corresponding":false},{"id":259581,"name":"Youssef Errami","orcid":"0000-0002-0432-4331","position":9,"is_corresponding":false},{"id":771900,"name":"Terence Wu","orcid":"0000-0001-6378-2116","position":10,"is_corresponding":false},{"id":259580,"name":"Paul Clark","orcid":"0009-0008-8399-5491","position":11,"is_corresponding":false},{"id":259570,"name":"Lupeng Ye","orcid":"0000-0003-3901-6598","position":12,"is_corresponding":false},{"id":842669,"name":"Quanjun Yang","orcid":"0000-0003-0279-8784","position":13,"is_corresponding":false},{"id":60778,"name":"Sidi Chen","orcid":"0000-0002-3819-5005","position":14,"is_corresponding":false},{"id":259572,"name":"Paul Renauer","orcid":"0000-0002-8747-0552","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:19:47.744358Z","pmid":"36993638","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":[]}