{"doi":"10.1038/s41467-024-50441-7","title":"Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8+ T cell activation and limit responsiveness to immunotherapy in mice","abstract":"Abstract Senescent cells within tumors and their stroma exert complex pro- and anti-tumorigenic functions. However, the identities and traits of these cells, and the potential for improving cancer therapy through their targeting, remain poorly characterized. Here, we identify a senescent subset within previously-defined cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinomas (PDAC) and in premalignant lesions in mice and humans. Senescent CAFs isolated from mouse and humans expressed elevated levels of immune-regulatory genes. Depletion of senescent CAFs, either genetically or using the Bcl-2 inhibitor ABT-199 (venetoclax), increased the proportion of activated CD8 + T cells in mouse pancreatic carcinomas, whereas induction of CAF senescence had the opposite effect. Combining ABT-199 with an immune checkpoint therapy regimen significantly reduced mouse tumor burden. These results indicate that senescent CAFs in PDAC stroma limit the numbers of activated cytotoxic CD8 + T cells, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy.","journal":"Nature Communications","year":2024,"id":417144,"datarank":1.4330285382400272,"base_score":4.394449154672439,"endowment":4.394449154672439,"self_citation_contribution":0.6591673732008659,"citation_network_contribution":0.7738611650391612,"self_endowment_contribution":0.6591673732008659,"citer_contribution":0.7738611650391612,"corpus_percentile":null,"corpus_rank":null,"citation_count":80,"citer_count":78,"citers_with_citation_signal":48,"citers_with_endowment":48,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9407,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE235246"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":593218,"name":"Rachel E. Kahn","orcid":"0000-0002-2888-355X","position":1,"is_corresponding":false},{"id":1203359,"name":"Lutfi Hodali","orcid":null,"position":2,"is_corresponding":false},{"id":32321,"name":"Reba Condiotti","orcid":null,"position":3,"is_corresponding":false},{"id":1203360,"name":"Yarden Engel","orcid":null,"position":4,"is_corresponding":false},{"id":622027,"name":"Ela Elyada","orcid":null,"position":5,"is_corresponding":false},{"id":1203361,"name":"Tzlil Mordechai-Heyn","orcid":null,"position":6,"is_corresponding":false},{"id":296416,"name":"Jason R. Pitarresi","orcid":"0000-0001-9549-4768","position":7,"is_corresponding":false},{"id":1202559,"name":"Dikla Atias","orcid":"0000-0003-3362-025X","position":8,"is_corresponding":false},{"id":1202560,"name":"Eliana Steinberg","orcid":"0009-0009-1743-8803","position":9,"is_corresponding":false},{"id":1203362,"name":"Tirza Bidany-Mizrahi","orcid":null,"position":10,"is_corresponding":false},{"id":1203363,"name":"Esther Forkosh","orcid":null,"position":11,"is_corresponding":false},{"id":275159,"name":"Lior H. Katz","orcid":"0000-0003-2885-7279","position":12,"is_corresponding":false},{"id":594642,"name":"Ofra Benny","orcid":"0000-0002-2468-5978","position":13,"is_corresponding":false},{"id":104680,"name":"Talia Golan","orcid":"0000-0001-5939-7012","position":14,"is_corresponding":false},{"id":2688,"name":"Matan Hofree","orcid":"0000-0001-8368-0299","position":15,"is_corresponding":false},{"id":103975,"name":"Sheila A. Stewart","orcid":"0000-0002-2260-9576","position":16,"is_corresponding":false},{"id":239094,"name":"Karine Atlan","orcid":null,"position":17,"is_corresponding":false},{"id":1202561,"name":"Gideon Zamir","orcid":"0000-0003-3133-863X","position":18,"is_corresponding":false},{"id":106462,"name":"Ben Z. Stanger","orcid":"0000-0003-0410-4037","position":19,"is_corresponding":false},{"id":208557,"name":"Michael Berger","orcid":"0000-0002-3469-0076","position":20,"is_corresponding":false},{"id":32335,"name":"Ittai Ben‐Porath","orcid":"0000-0001-7815-1165","position":21,"is_corresponding":false},{"id":746358,"name":"Benjamin Assouline","orcid":"0000-0002-9070-5834","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T01:56:50.743370Z","pmid":"39039076","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":[]}