{"doi":"10.1172/jci.insight.168824","title":"Potentiating the radiation-induced type I interferon antitumoral immune response by ATM inhibition in pancreatic cancer","abstract":"Radiotherapy induces a type I interferon-mediated (T1IFN-mediated) antitumoral immune response that we hypothesized could be potentiated by a first-in-class ataxia telangiectasia mutated (ATM) inhibitor, leading to enhanced innate immune signaling, T1IFN expression, and sensitization to immunotherapy in pancreatic cancer. We evaluated the effects of AZD1390 or a structurally related compound, AZD0156, on innate immune signaling and found that both inhibitors enhanced radiation-induced T1IFN expression via the POLIII/RIG-I/MAVS pathway. In immunocompetent syngeneic mouse models of pancreatic cancer, ATM inhibitor enhanced radiation-induced antitumoral immune responses and sensitized tumors to anti-PD-L1, producing immunogenic memory and durable tumor control. Therapeutic responses were associated with increased intratumoral CD8+ T cell frequency and effector function. Tumor control was dependent on CD8+ T cells, as therapeutic efficacy was blunted in CD8+ T cell-depleted mice. Adaptive immune responses to combination therapy provided systemic control of contralateral tumors outside of the radiation field. Taken together, we show that a clinical candidate ATM inhibitor enhances radiation-induced T1IFN, leading to both innate and subsequent adaptive antitumoral immune responses and sensitization of otherwise resistant pancreatic cancer to immunotherapy.","journal":"JCI Insight","year":2024,"id":431407,"datarank":0.4335557636844247,"base_score":2.8903717578961645,"endowment":2.8903717578961645,"self_citation_contribution":0.4335557636844247,"citation_network_contribution":0.0,"self_endowment_contribution":0.4335557636844247,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":17,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9547,"is_data_producer":false,"deposit_databanks":null,"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":614802,"name":"Long Jiang","orcid":"0000-0003-4607-8068","position":1,"is_corresponding":false},{"id":251054,"name":"Weiwei Wang","orcid":"0000-0003-0333-0868","position":2,"is_corresponding":false},{"id":250806,"name":"Amanda K. Huber","orcid":"0000-0003-0375-8709","position":3,"is_corresponding":false},{"id":1169697,"name":"Victoria M. Valvo","orcid":"0009-0004-5837-4141","position":4,"is_corresponding":false},{"id":748711,"name":"Kassidy M. Jungles","orcid":"0000-0001-5705-8455","position":5,"is_corresponding":false},{"id":443396,"name":"Erin A. Holcomb","orcid":"0000-0003-1368-9858","position":6,"is_corresponding":false},{"id":1071859,"name":"Ashley N. Pearson","orcid":"0000-0002-4583-2682","position":7,"is_corresponding":false},{"id":225396,"name":"Stephanie The","orcid":"0000-0002-6660-4136","position":8,"is_corresponding":false},{"id":739792,"name":"Zhuwen Wang","orcid":"0000-0002-8757-7392","position":9,"is_corresponding":false},{"id":458754,"name":"Leslie A. Parsels","orcid":"0000-0002-5880-1033","position":10,"is_corresponding":false},{"id":460134,"name":"Joshua D. Parsels","orcid":null,"position":11,"is_corresponding":false},{"id":238050,"name":"Daniel Wahl","orcid":"0000-0001-9894-5085","position":12,"is_corresponding":false},{"id":69715,"name":"Arvind Rao","orcid":"0000-0002-9613-426X","position":13,"is_corresponding":false},{"id":225417,"name":"Vaibhav Sahai","orcid":"0000-0003-1892-1548","position":14,"is_corresponding":false},{"id":238049,"name":"Theodore S. Lawrence","orcid":"0000-0002-4186-8821","position":15,"is_corresponding":false},{"id":246394,"name":"Michael D. Green","orcid":"0000-0003-4951-7118","position":16,"is_corresponding":false},{"id":238047,"name":"Meredith A. Morgan","orcid":"0000-0001-7965-6878","position":17,"is_corresponding":false},{"id":1078676,"name":"Qiang Zhang","orcid":"0000-0001-5008-4327","position":0,"is_corresponding":true}],"reference_count":80,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:59:25.642507Z","pmid":"38376927","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":[]}