{"doi":"10.4049/jimmunol.2000765","title":"CD40 Agonist Overcomes T Cell Exhaustion Induced by Chronic Myeloid Cell IL-27 Production in a Pancreatic Cancer Preclinical Model","abstract":"Abstract Pancreatic cancer is a particularly lethal malignancy that resists immunotherapy. In this study, using a preclinical pancreatic cancer murine model, we demonstrate a progressive decrease in IFN-γ and granzyme B and a concomitant increase in Tox and IL-10 in intratumoral tumor-specific T cells. Intratumoral myeloid cells produced elevated IL-27, a cytokine that correlates with poor patient outcome. Abrogating IL-27 signaling significantly decreased intratumoral Tox+ T cells and delayed tumor growth yet was not curative. Agonistic αCD40 decreased intratumoral IL-27–producing myeloid cells, decreased IL-10–producing intratumoral T cells, and promoted intratumoral Klrg1+Gzmb+ short-lived effector T cells. Combination agonistic αCD40+αPD-L1 cured 63% of tumor-bearing animals, promoted rejection following tumor rechallenge, and correlated with a 2-log increase in pancreas-residing tumor-specific T cells. Interfering with Ifngr1 expression in nontumor/host cells abrogated agonistic αCD40+αPD-L1 efficacy. In contrast, interfering with nontumor/host cell Tnfrsf1a led to cure in 100% of animals following agonistic αCD40+αPD-L1 and promoted the formation of circulating central memory T cells rather than long-lived effector T cells. In summary, we identify a mechanistic basis for T cell exhaustion in pancreatic cancer and a feasible clinical strategy to overcome it.","journal":"The Journal of Immunology","year":2021,"id":165607,"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":35,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9514,"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":640611,"name":"Meagan R. Rollins","orcid":"0000-0002-9459-6890","position":1,"is_corresponding":false},{"id":689378,"name":"Ellen J. Spartz","orcid":"0000-0001-6750-2441","position":2,"is_corresponding":false},{"id":690144,"name":"Taylor D. Mesojednik","orcid":null,"position":3,"is_corresponding":false},{"id":658616,"name":"Zoe C. Schmiechen","orcid":"0000-0002-3403-6824","position":4,"is_corresponding":false},{"id":690145,"name":"Jackson F. Raynor","orcid":null,"position":5,"is_corresponding":false},{"id":689379,"name":"Iris Wang","orcid":"0000-0003-1869-885X","position":6,"is_corresponding":false},{"id":351178,"name":"Ross M. Kedl","orcid":"0000-0002-9065-7895","position":7,"is_corresponding":false},{"id":513391,"name":"Ingunn M. Stromnes","orcid":"0000-0001-8120-4547","position":8,"is_corresponding":false},{"id":445732,"name":"Adam L. Burrack","orcid":"0000-0002-4001-7849","position":0,"is_corresponding":true}],"reference_count":96,"raw_metadata":null,"created_at":"2026-07-18T23:45:40.838485Z","pmid":"33558374","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":[]}