{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T22:47:05Z","timestamp":1793832425922,"version":"4.6.1"},"reference-count":50,"publisher":"BMJ","issue":"2","license":[{"start":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T00:00:00Z","timestamp":1594857600000},"content-version":"unspecified","delay-in-days":15,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Survival with Pancreatic Cancer Foundation","award":["OVIT 17-04"],"award-info":[{"award-number":["OVIT 17-04"]}]},{"name":"Survival with Pancreatic Cancer Foundation","award":["OVIT-17-06"],"award-info":[{"award-number":["OVIT-17-06"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2020,6,9]]},"published-print":{"date-parts":[[2020,7]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Pancreatic ductal adenocarcinoma (PDAC) is notoriously resistant to treatment including checkpoint-blockade immunotherapy. We hypothesized that a bimodal treatment approach consisting of dendritic cell (DC) vaccination to prime tumor-specific T cells, and a strategy to reprogram the desmoplastic tumor microenvironment (TME) would be needed to break tolerance to these pancreatic cancers. As a proof-of-concept, we investigated the efficacy of combined DC vaccination with CD40-agonistic antibodies in a poorly immunogenic murine model of PDAC. Based on the rationale that mesothelioma and pancreatic cancer share a number of tumor associated antigens, the DCs were loaded with either pancreatic or mesothelioma tumor lysates.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Immune-competent mice with subcutaneously or orthotopically growing KrasG12D\/+;Trp53R172H\/+;Pdx-1-Cre (KPC) PDAC tumors were vaccinated with syngeneic bone marrow-derived DCs loaded with either pancreatic cancer (KPC) or mesothelioma (AE17) lysate and consequently treated with FGK45 (CD40 agonist). Tumor progression was monitored and immune responses in TME and lymphoid organs were analyzed using multicolor flow cytometry and NanoString analyzes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Mesothelioma-lysate loaded DCs generated cross-reactive tumor-antigen-specific T-cell responses to pancreatic cancer and induced delayed tumor outgrowth when provided as prophylactic vaccine. In established disease, combination with stimulating CD40 antibody was necessary to improve survival, while anti-CD40 alone was ineffective. Extensive analysis of the TME showed that anti-CD40 monotherapy did improve CD8 +T\u2009cell infiltration, but these essential effector cells displayed hallmarks of exhaustion, including PD-1, TIM-3 and NKG2A. Combination therapy induced a strong change in tumor transcriptome and mitigated the expression of inhibitory markers on CD8 +T cells.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>These results demonstrate the potency of DC therapy in combination with CD40-stimulation for the treatment of pancreatic cancer and provide directions for near future clinical trials.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2020-000772","type":"journal-article","created":{"date-parts":[[2020,7,21]],"date-time":"2020-07-21T02:04:47Z","timestamp":1595297087000},"page":"e000772","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":64,"title":["Dendritic cell vaccination and CD40-agonist combination therapy licenses T cell-dependent antitumor immunity in a pancreatic carcinoma murine model"],"prefix":"10.1136","volume":"8","clinical-trial-number":[{"clinical-trial-number":"nct03214250","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02588443","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03329950","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6876-220X","authenticated-orcid":false,"given":"Sai Ping","family":"Lau","sequence":"first","affiliation":[{"name":"Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands"},{"name":"Department of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7906-7202","authenticated-orcid":false,"given":"Nadine","family":"van Montfoort","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priscilla","family":"Kinderman","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Lukkes","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larissa","family":"Klaase","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menno","family":"van Nimwegen","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandy","family":"van Gulijk","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasper","family":"Dumas","sequence":"additional","affiliation":[{"name":"Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana A M","family":"Mustafa","sequence":"additional","affiliation":[{"name":"Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanne L A","family":"Lievense","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Amphia Hospital, Breda, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1742-1517","authenticated-orcid":false,"given":"Christianne","family":"Groeneveldt","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph","family":"Stadhouders","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, The Netherlands"},{"name":"Department of Cell Biology, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunlei","family":"Li","sequence":"additional","affiliation":[{"name":"Clinical Bioinformatics Unit, Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9817-9982","authenticated-orcid":false,"given":"Andrew","family":"Stubbs","sequence":"additional","affiliation":[{"name":"Clinical Bioinformatics Unit, Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koen A","family":"Marijt","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4392-935X","authenticated-orcid":false,"given":"Heleen","family":"Vroman","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sjoerd H","family":"van der Burg","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"Aerts","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, The Netherlands"},{"name":"Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9115-558X","authenticated-orcid":false,"given":"Thorbald","family":"van Hall","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Floris","family":"Dammeijer","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus Medical 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