{"doi":"10.1158/2159-8290.cd-21-1586","title":"Sequential Single-Cell Transcriptional and Protein Marker Profiling Reveals TIGIT as a Marker of CD19 CAR-T Cell Dysfunction in Patients with Non-Hodgkin Lymphoma","abstract":"Chimeric antigen receptor T-cell (CAR-T cell) therapy directed at CD19 produces durable remissions in the treatment of relapsed/refractory non-Hodgkin lymphoma (NHL). Nonetheless, many patients receiving CD19 CAR-T cells fail to respond for unknown reasons. To reveal changes in 4-1BB-based CD19 CAR-T cells and identify biomarkers of response, we used single-cell RNA sequencing and protein surface marker profiling of patient CAR-T cells pre- and postinfusion into patients with NHL. At the transcriptional and protein levels, we note the evolution of CAR-T cells toward a nonproliferative, highly differentiated, and exhausted state, with an enriched exhaustion profile in CAR-T cells of patients with poor response marked by TIGIT expression. Utilizing in vitro and in vivo studies, we demonstrate that TIGIT blockade alone improves the antitumor function of CAR-T cells. Altogether, we provide evidence of CAR-T cell dysfunction marked by TIGIT expression driving a poor response in patients with NHL. SIGNIFICANCE: This is the first study investigating the mechanisms linked to CAR-T patient responses based on the sequential analysis of manufactured and infused CAR-T cells using single-cell RNA and protein expression data. Furthermore, our findings are the first to demonstrate an improvement of CAR-T cell efficacy with TIGIT inhibition alone. This article is highlighted in the In This Issue feature, p. 1825.","journal":"Cancer Discovery","year":2022,"id":234953,"datarank":0.6732954554598211,"base_score":4.48863636973214,"endowment":4.48863636973214,"self_citation_contribution":0.6732954554598211,"citation_network_contribution":0.0,"self_endowment_contribution":0.6732954554598211,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":88,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9558,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":240678,"name":"Changjin Hong","orcid":"0000-0002-9671-2226","position":1,"is_corresponding":false},{"id":851705,"name":"Robert Schauner","orcid":"0000-0002-6336-7331","position":2,"is_corresponding":false},{"id":257080,"name":"Boro Dropulić","orcid":"0000-0002-3861-7677","position":3,"is_corresponding":false},{"id":105210,"name":"Paolo F. Caimi","orcid":"0000-0003-1436-0464","position":4,"is_corresponding":false},{"id":339781,"name":"Marcos de Lima","orcid":"0000-0002-8568-4522","position":5,"is_corresponding":false},{"id":851706,"name":"Maria Florencia Giraudo","orcid":"0000-0003-0751-1690","position":6,"is_corresponding":false},{"id":291042,"name":"Kalpana Gupta","orcid":"0000-0002-6766-3576","position":7,"is_corresponding":false},{"id":851707,"name":"Jane Reese","orcid":"0000-0002-0337-5372","position":8,"is_corresponding":false},{"id":240690,"name":"Tae Hyun Hwang","orcid":"0000-0002-6668-7269","position":9,"is_corresponding":false},{"id":598105,"name":"David N. Wald","orcid":null,"position":10,"is_corresponding":false},{"id":781359,"name":"Zachary Jackson","orcid":"0000-0003-3655-8279","position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:21:42.662304Z","pmid":"35554512","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":[]}