{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T01:44:03Z","timestamp":1790905443862,"version":"4.1.0"},"reference-count":49,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T00:00:00Z","timestamp":1625443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","award":["109255"],"award-info":[{"award-number":["109255"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["GO 1847\/1-2"],"award-info":[{"award-number":["GO 1847\/1-2"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University Hospital of Bonn","award":["BONFOR"],"award-info":[{"award-number":["BONFOR"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Dendritic cells (DC) as professional antigen presenting cells are able to prime T-cells against the tumor-associated antigen \u03b1-fetoprotein (AFP) for immunotherapy of hepatocellular carcinoma (HCC). However, a strong immunosuppressive tumor environment limits their efficacy in patients. The co-stimulation with CD40Ligand (CD40L) is critical in the maturation of DC and T-cell priming. In this study, the impact of intratumoral (i.t.) CD40L-expressing DC to improve vaccination with murine (m)AFP-transduced DC (Ad-mAFP-DC) was analyzed in subcutaneous (s.c.) and orthotopic murine HCC. Murine DC were adenovirally transduced with Ad-mAFP or Ad-CD40L. Hepa129-mAFP-cells were injected into the right flank or the liver of C3H-mice to induce subcutaneous (s.c.) and orthotopic HCC. For treatments, 106 Ad-mAFP-transduced DC were inoculated s.c. followed by 106 CD40L-expressing DC injected intratumorally (i.t.). S.c. inoculation with Ad-mAFP-transduced DC, as vaccine, induced a delay of tumor-growth of AFP-positive HCC compared to controls. When s.c.-inoculation of Ad-mAFP-DC was combined with i.t.-application of Ad-CD40L-DC synergistic antitumoral effects were observed and complete remissions and long-term survival in 62% of tumor-bearing animals were achieved. Analysis of the tumor environment at different time points revealed that s.c.-vaccination with Ad-mAFP-DC seems to stimulate tumor-specific effector cells, allowing an earlier recruitment of effector T-cells and a Th1 shift within the tumors. After i.t. co-stimulation with Ad-CD40L-DC, production of Th1-cytokines was strongly increased and accompanied by a robust tumor infiltration of mature DC, activated CD4+-, CD8+-T-cells as well as reduction of regulatory T-cells. Moreover, Ad-CD40L-DC induced tumor cell apoptosis. Intratumoral co-stimulation with CD40L-expressing DC significantly improves vaccination with Ad-mAFP-DC in pre-established HCC in vivo. Combined therapy caused an early and strong Th1-shift in the tumor environment as well as higher tumor apoptosis, leading to synergistic tumor regression of HCC. Thus, CD40L co-stimulation represents a promising tool for improving DC-based immunotherapy of HCC.<\/jats:p>","DOI":"10.3390\/cancers13133375","type":"journal-article","created":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T22:02:04Z","timestamp":1625522524000},"page":"3375","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Alpha-Fetoprotein- and CD40Ligand-Expressing Dendritic Cells for Immunotherapy of Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"13","author":[{"given":"Annabelle","family":"Vogt","sequence":"first","affiliation":[{"name":"Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farsaneh","family":"Sadeghlar","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiyasha H.","family":"Ayub","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7651-4401","authenticated-orcid":false,"given":"Christian","family":"M\u00f6hring","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taotao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8312-6511","authenticated-orcid":false,"given":"Robert","family":"Mahn","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Bartels","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7033-9956","authenticated-orcid":false,"given":"Michael","family":"Praktiknjo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1682-1765","authenticated-orcid":false,"given":"Miroslaw T.","family":"Kornek","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marieta","family":"Toma","sequence":"additional","affiliation":[{"name":"Department of Pathology, University Hospital of Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingo G. H.","family":"Schmidt-Wolf","sequence":"additional","affiliation":[{"name":"Department of Integrated Oncology (CIO), University of Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6182-835X","authenticated-orcid":false,"given":"Vittorio","family":"Branchi","sequence":"additional","affiliation":[{"name":"Department of Visceral Surgery, University Hospital of Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanno","family":"Matthaei","sequence":"additional","affiliation":[{"name":"Department of Visceral Surgery, University Hospital of Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg C.","family":"Kalff","sequence":"additional","affiliation":[{"name":"Department of Visceral Surgery, University Hospital of Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian P.","family":"Strassburg","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3956-1457","authenticated-orcid":false,"given":"Maria A.","family":"Gonzalez-Carmona","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1002\/hep.31288","article-title":"Epidemiology of hepatocellular carcinoma","volume":"73","author":"Petrick","year":"2021","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"171","DOI":"10.3389\/fonc.2020.00171","article-title":"Global trends in incidence rates of primary adult liver cancers: A systematic review and meta-analysis","volume":"10","author":"Dasgupta","year":"2020","journal-title":"Front. 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