Alpha-Fetoprotein- and CD40Ligand-Expressing Dendritic Cells for Immunotherapy of Hepatocellular Carcinoma
Dendritic cells (DC) as professional antigen presenting cells are able to prime T-cells against the tumor-associated antigen α-fetoprotein (AFP) for immunotherapy of hepatocellular carcinoma (HCC). However, a strong immunosuppressive tumor environment limits their efficacy in patients. The co-stimul...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-07-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/13/3375 |
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| author | Annabelle Vogt Farsaneh Sadeghlar Tiyasha H. Ayub Carlo Schneider Christian Möhring Taotao Zhou Robert Mahn Alexandra Bartels Michael Praktiknjo Miroslaw T. Kornek Marieta Toma Ingo G. H. Schmidt-Wolf Vittorio Branchi Hanno Matthaei Jörg C. Kalff Christian P. Strassburg Maria A. Gonzalez-Carmona |
| author_facet | Annabelle Vogt Farsaneh Sadeghlar Tiyasha H. Ayub Carlo Schneider Christian Möhring Taotao Zhou Robert Mahn Alexandra Bartels Michael Praktiknjo Miroslaw T. Kornek Marieta Toma Ingo G. H. Schmidt-Wolf Vittorio Branchi Hanno Matthaei Jörg C. Kalff Christian P. Strassburg Maria A. Gonzalez-Carmona |
| author_sort | Annabelle Vogt |
| collection | DOAJ |
| description | Dendritic cells (DC) as professional antigen presenting cells are able to prime T-cells against the tumor-associated antigen α-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, 10<sup>6</sup> Ad-mAFP-transduced DC were inoculated s.c. followed by 10<sup>6</sup> 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<sup>+</sup>-, CD8<sup>+</sup>-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. |
| first_indexed | 2024-03-10T09:52:40Z |
| format | Article |
| id | doaj.art-401131db7af3463584c2c76e33319524 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T09:52:40Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-401131db7af3463584c2c76e333195242023-11-22T02:36:53ZengMDPI AGCancers2072-66942021-07-011313337510.3390/cancers13133375Alpha-Fetoprotein- and CD40Ligand-Expressing Dendritic Cells for Immunotherapy of Hepatocellular CarcinomaAnnabelle Vogt0Farsaneh Sadeghlar1Tiyasha H. Ayub2Carlo Schneider3Christian Möhring4Taotao Zhou5Robert Mahn6Alexandra Bartels7Michael Praktiknjo8Miroslaw T. Kornek9Marieta Toma10Ingo G. H. Schmidt-Wolf11Vittorio Branchi12Hanno Matthaei13Jörg C. Kalff14Christian P. Strassburg15Maria A. Gonzalez-Carmona16Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, GermanyDepartment of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, GermanyDepartment of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, GermanyDepartment of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, GermanyDepartment of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, GermanyDepartment of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, GermanyDepartment of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, GermanyDepartment of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, GermanyDepartment of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, GermanyDepartment of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, GermanyDepartment of Pathology, University Hospital of Bonn, 53127 Bonn, GermanyDepartment of Integrated Oncology (CIO), University of Bonn, 53127 Bonn, GermanyDepartment of Visceral Surgery, University Hospital of Bonn, 53127 Bonn, GermanyDepartment of Visceral Surgery, University Hospital of Bonn, 53127 Bonn, GermanyDepartment of Visceral Surgery, University Hospital of Bonn, 53127 Bonn, GermanyDepartment of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, GermanyDepartment of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, GermanyDendritic cells (DC) as professional antigen presenting cells are able to prime T-cells against the tumor-associated antigen α-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, 10<sup>6</sup> Ad-mAFP-transduced DC were inoculated s.c. followed by 10<sup>6</sup> 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<sup>+</sup>-, CD8<sup>+</sup>-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.https://www.mdpi.com/2072-6694/13/13/3375alpha-fetoproteinCD40Liganddendritic cellshepatocellular carcinomasubcutaneous and orthotopic murine HCC |
| spellingShingle | Annabelle Vogt Farsaneh Sadeghlar Tiyasha H. Ayub Carlo Schneider Christian Möhring Taotao Zhou Robert Mahn Alexandra Bartels Michael Praktiknjo Miroslaw T. Kornek Marieta Toma Ingo G. H. Schmidt-Wolf Vittorio Branchi Hanno Matthaei Jörg C. Kalff Christian P. Strassburg Maria A. Gonzalez-Carmona Alpha-Fetoprotein- and CD40Ligand-Expressing Dendritic Cells for Immunotherapy of Hepatocellular Carcinoma Cancers alpha-fetoprotein CD40Ligand dendritic cells hepatocellular carcinoma subcutaneous and orthotopic murine HCC |
| title | Alpha-Fetoprotein- and CD40Ligand-Expressing Dendritic Cells for Immunotherapy of Hepatocellular Carcinoma |
| title_full | Alpha-Fetoprotein- and CD40Ligand-Expressing Dendritic Cells for Immunotherapy of Hepatocellular Carcinoma |
| title_fullStr | Alpha-Fetoprotein- and CD40Ligand-Expressing Dendritic Cells for Immunotherapy of Hepatocellular Carcinoma |
| title_full_unstemmed | Alpha-Fetoprotein- and CD40Ligand-Expressing Dendritic Cells for Immunotherapy of Hepatocellular Carcinoma |
| title_short | Alpha-Fetoprotein- and CD40Ligand-Expressing Dendritic Cells for Immunotherapy of Hepatocellular Carcinoma |
| title_sort | alpha fetoprotein and cd40ligand expressing dendritic cells for immunotherapy of hepatocellular carcinoma |
| topic | alpha-fetoprotein CD40Ligand dendritic cells hepatocellular carcinoma subcutaneous and orthotopic murine HCC |
| url | https://www.mdpi.com/2072-6694/13/13/3375 |
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