{"doi":"10.1136/jitc-2020-001877","title":"Designed improvement to T-cell immunotherapy by multidimensional single cell profiling","abstract":"Background Adoptive cell therapy based on the infusion of chimeric antigen receptor (CAR) T cells has shown remarkable efficacy for the treatment of hematologic malignancies. The primary mechanism of action of these infused T cells is the direct killing of tumor cells expressing the cognate antigen. However, understanding why only some T cells are capable of killing, and identifying mechanisms that can improve killing has remained elusive. Methods To identify molecular and cellular mechanisms that can improve T-cell killing, we utilized integrated high-throughput single-cell functional profiling by microscopy, followed by robotic retrieval and transcriptional profiling. Results With the aid of mathematical modeling we demonstrate that non-killer CAR T cells comprise a heterogeneous population that arise from failure in each of the discrete steps leading to the killing. Differential transcriptional single-cell profiling of killers and non-killers identified CD137 as an inducible costimulatory molecule upregulated on killer T cells. Our single-cell profiling results directly demonstrate that inducible CD137 is feature of killer (and serial killer) T cells and this marks a different subset compared with the CD107a pos (degranulating) subset of CAR T cells. Ligation of the induced CD137 with CD137 ligand (CD137L) leads to younger CD19 CAR T cells with sustained killing and lower exhaustion. We genetically modified CAR T cells to co-express CD137L, in trans, and this lead to a profound improvement in anti-tumor efficacy in leukemia and refractory ovarian cancer models in mice. Conclusions Broadly, our results illustrate that while non-killer T cells are reflective of population heterogeneity, integrated single-cell profiling can enable identification of mechanisms that can enhance the function/proliferation of killer T cells leading to direct anti-tumor benefit.","journal":"Journal for ImmunoTherapy of Cancer","year":2021,"id":171531,"datarank":0.4943755299006494,"base_score":3.295836866004329,"endowment":3.295836866004329,"self_citation_contribution":0.4943755299006494,"citation_network_contribution":0.0,"self_endowment_contribution":0.4943755299006494,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9526,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":655601,"name":"Jay R T. Adolacion","orcid":"0000-0003-1091-8192","position":1,"is_corresponding":false},{"id":706997,"name":"Gabrielle Romain","orcid":null,"position":2,"is_corresponding":false},{"id":249834,"name":"Melisa Martinez-Paniagua","orcid":"0000-0002-7275-4317","position":3,"is_corresponding":false},{"id":249830,"name":"Xingyue An","orcid":"0000-0001-9912-0683","position":4,"is_corresponding":false},{"id":667146,"name":"Arash Saeedi","orcid":null,"position":5,"is_corresponding":false},{"id":706271,"name":"Ivan Liadi","orcid":"0000-0003-3830-6569","position":6,"is_corresponding":false},{"id":706998,"name":"Zheng You","orcid":null,"position":7,"is_corresponding":false},{"id":706272,"name":"Rasindu B Rajanayake","orcid":"0000-0002-3358-4407","position":8,"is_corresponding":false},{"id":320447,"name":"Patrick Hwu","orcid":"0000-0003-0554-2856","position":9,"is_corresponding":false},{"id":706273,"name":"Harjeet Singh","orcid":"0000-0001-6314-5790","position":10,"is_corresponding":false},{"id":418810,"name":"Laurence J.N. Cooper","orcid":"0000-0003-1460-3905","position":11,"is_corresponding":false},{"id":18360,"name":"Navin Varadarajan","orcid":"0000-0001-7524-8228","position":12,"is_corresponding":false},{"id":706270,"name":"Irfan Bandey","orcid":"0000-0002-9330-2432","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:46:33.067299Z","pmid":"33722906","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":[]}