{"doi":"10.1101/2020.07.08.194332","title":"Mapping the evolution of T cell states during response and resistance to adoptive cellular therapy","abstract":"Immune therapies have transformed the cancer therapeutic landscape but fail to benefit most patients. To elucidate the underlying mechanisms by which T cells mediate elimination of leukemia, we generated a high-resolution map of longitudinal T cell dynamics within the same tumor microenvironment (TME) during response or resistance to donor lymphocyte infusion (DLI), a widely used immunotherapy for relapsed leukemia. We analyzed 87,939 bone marrow-derived single T cell transcriptomes, along with chromatin accessibility and single T cell receptor clonality profiles, by developing novel machine learning tools for integrating longitudinal and multimodal data. We found that pre-treatment enrichment and post-treatment rapid, durable expansion of ‘terminal’ (T EX ) and ‘precursor’ (T PEX ) exhausted subsets, respectively, defined DLI response. A contrasting, heterogeneous pattern of T cell dysfunction marked DLI resistance. Unexpectedly, T PEX cells that expanded in responders did not arise from the infusion product but instead from both pre-existing and novel clonotypes recruited to the TME. Our unbiased dissection of the TME using a Bayesian method, Symphony, defined the T cell circuitry underlying effective human anti-leukemic immune responses that may be broadly relevant to other exhaustion antagonists across cancers. Finally, we provide a general analysis paradigm for exploiting temporal single-cell genomic profiling for deep understanding of therapeutic scenarios beyond oncology.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":120948,"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":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9403,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":559371,"name":"Elham Azizi","orcid":"0000-0001-5059-6971","position":1,"is_corresponding":false},{"id":559372,"name":"Cassandra Burdziak","orcid":"0000-0001-6008-7783","position":2,"is_corresponding":false},{"id":396151,"name":"Vinhkhang N. Nguyen","orcid":null,"position":3,"is_corresponding":false},{"id":394795,"name":"Christina Ennis","orcid":"0000-0003-0316-4003","position":4,"is_corresponding":false},{"id":306547,"name":"Zi-Ning Choo","orcid":null,"position":5,"is_corresponding":false},{"id":25286,"name":"Shuqiang Li","orcid":"0000-0003-4507-5922","position":6,"is_corresponding":false},{"id":12216,"name":"Kenneth J. Livak","orcid":"0000-0001-9105-5856","position":7,"is_corresponding":false},{"id":3266,"name":"Donna Neuberg","orcid":"0000-0003-2566-3145","position":8,"is_corresponding":false},{"id":282402,"name":"Robert J. Soiffer","orcid":"0000-0002-5810-1192","position":9,"is_corresponding":false},{"id":34475,"name":"Jerome Ritz","orcid":"0000-0001-5526-4669","position":10,"is_corresponding":false},{"id":282401,"name":"Edwin P. Alyea","orcid":"0000-0002-1885-8430","position":11,"is_corresponding":false},{"id":104368,"name":"Dana Pe’er","orcid":"0000-0002-9259-8817","position":12,"is_corresponding":false},{"id":3263,"name":"Catherine J. Wu","orcid":"0000-0002-3348-5054","position":13,"is_corresponding":false},{"id":44978,"name":"Pavan Bachireddy","orcid":"0000-0002-8698-4957","position":0,"is_corresponding":true}],"reference_count":86,"raw_metadata":null,"created_at":"2026-07-18T23:14:38.147936Z","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":[]}