{"doi":"10.1084/jem.20230542","title":"PD-1 regulates tumor-infiltrating CD8+ T cells in both a cell-intrinsic and a cell-extrinsic fashion","abstract":"Although PD-1 inhibitors are FDA-approved for over 25 different cancers, the mechanisms contributing to response remain incompletely understood. To investigate how PD-1-deleted CD8+ T cells influence PD-1-expressing CD8+ T cells in the same tumor microenvironment, we developed an inducible PD-1 knockout (KO) model in which PD-1 is deleted on ∼50% of cells. PD-1 deletion beginning at day 7 after implantation of MC38 tumor cells led to robust tumor control. Remarkably, PD-1-expressing CD8+ T cells in the tumor had increased functionality similar to PD-1 KO CD8+ T cells. Using single-cell RNA-seq and TCR-seq, we found that the major transcriptional changes following PD-1 deletion were shared by PD-1 KO and PD-1-expressing CD8+ T cells, although PD-1 KO clones preferentially expanded. These data suggest PD-1 inhibitors not only exert cell-intrinsic effects but also may promote increased T cell function through non-cell-autonomous mechanisms, which has important implications for design of PD-1-based cancer immunotherapies.","journal":"The Journal of Experimental Medicine","year":2025,"id":519923,"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":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9587,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":651007,"name":"Samuel C. Markson","orcid":"0000-0001-9053-9867","position":1,"is_corresponding":false},{"id":1044171,"name":"Thomas S. Conway","orcid":"0009-0006-9757-5995","position":2,"is_corresponding":false},{"id":108664,"name":"Vikram R. Juneja","orcid":"0000-0001-6011-6417","position":3,"is_corresponding":false},{"id":267959,"name":"Osmaan Shahid","orcid":"0000-0002-3694-8480","position":4,"is_corresponding":false},{"id":4522,"name":"Kelly P. Burke","orcid":"0000-0003-2187-0147","position":5,"is_corresponding":false},{"id":391315,"name":"Jared H. Rowe","orcid":"0000-0002-4223-4433","position":6,"is_corresponding":false},{"id":108665,"name":"Thao H. Nguyen","orcid":"0000-0002-2767-0528","position":7,"is_corresponding":false},{"id":621412,"name":"Jenna L. Collier","orcid":"0000-0002-4071-4986","position":8,"is_corresponding":false},{"id":267963,"name":"Jaclyn M. Long","orcid":"0000-0001-6292-1006","position":9,"is_corresponding":false},{"id":267964,"name":"Megan E. Fung","orcid":"0000-0002-9053-0915","position":10,"is_corresponding":false},{"id":267962,"name":"Jacob M. Luber","orcid":"0000-0001-5268-5732","position":11,"is_corresponding":false},{"id":15336,"name":"Alison E. Ringel","orcid":"0000-0002-6451-9376","position":12,"is_corresponding":false},{"id":17249,"name":"Jason M. Schenkel","orcid":"0000-0003-4641-6872","position":13,"is_corresponding":false},{"id":4539,"name":"Gordon J. Freeman","orcid":"0000-0002-7210-5616","position":14,"is_corresponding":false},{"id":6945,"name":"Marcia C. Haigis","orcid":"0000-0003-2530-2681","position":15,"is_corresponding":false},{"id":34472,"name":"Meromit Singer","orcid":"0000-0002-1755-3598","position":16,"is_corresponding":false},{"id":4542,"name":"Arlene H. Sharpe","orcid":"0000-0002-9736-2109","position":17,"is_corresponding":false},{"id":61817,"name":"Kristen E. Pauken","orcid":"0000-0002-4309-7880","position":0,"is_corresponding":true}],"reference_count":81,"raw_metadata":null,"created_at":"2026-07-19T02:49:23.618703Z","pmid":"40705010","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":[]}