Plasmacytoid Dendritic Cells in the Tumor Microenvironment: Immune Targets for Glioma Therapeutics
Adenovirus-mediated delivery of the immune-stimulatory cytokine Flt3L and the conditionally cytotoxic thymidine kinase (TK) induces tumor regression and long-term survival in preclinical glioma (glioblastoma multiforme [GBM]) models. Flt3L induces expansion and recruitment of plasmacytoid dendritic...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2012-08-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558612800091 |
| _version_ | 1818807099535130624 |
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| author | Marianela Candolfi Gwendalyn D. King Kader Yagiz James F. Curtin Yohei Mineharu AKM Ghulam Muhammad David Foulad Kurt M. Kroeger Nick Barnett Regis Josien Pedro R. Lowenstein Maria G. Castro |
| author_facet | Marianela Candolfi Gwendalyn D. King Kader Yagiz James F. Curtin Yohei Mineharu AKM Ghulam Muhammad David Foulad Kurt M. Kroeger Nick Barnett Regis Josien Pedro R. Lowenstein Maria G. Castro |
| author_sort | Marianela Candolfi |
| collection | DOAJ |
| description | Adenovirus-mediated delivery of the immune-stimulatory cytokine Flt3L and the conditionally cytotoxic thymidine kinase (TK) induces tumor regression and long-term survival in preclinical glioma (glioblastoma multiforme [GBM]) models. Flt3L induces expansion and recruitment of plasmacytoid dendritic cells (pDCs) into the brain. Although pDCs can present antigen and produce powerful inflammatory cytokines, that is, interferon α (IFN-α), their role in tumor immunology remains debated. Thus, we studied the role of pDCs and IFN-α in Ad.TK/GCV+ Ad.Flt3L-mediated anti-GBM therapeutic efficacy. Our data indicate that the combined gene therapy induced recruitment of plasmacytoid DCs (pDCs) into the tumor mass; which were capable of in vivo phagocytosis, IFN-α release, and T-cell priming. Thus, we next used either pDCs or an Ad vector encoding IFN-α delivered within the tumor microenvironment. When rats were treated with Ad.TK/GCV in combination with pDCs or Ad-IFN-α, they exhibited 35% and 50% survival, respectively. However, whereas intracranial administration of Ad.TK/GCV + Ad.Flt3L exhibited a high safety profile, Ad-IFN-α led to severe local inflammation, with neurologic and systemic adverse effects. To elucidate whether the efficacy of the immunotherapy was dependent on IFN-α-secreting pDCs, we administered an Ad vector encoding B18R, an IFN-α antagonist, which abrogated the antitumoral effect of Ad.TK/GCV + Ad.Flt3L. Our data suggest that IFN-α release by activated pDCs plays a critical role in the antitumor effect mediated by Ad.TK/GCV + Ad.Flt3L. In summary, taken together, our results demonstrate that pDCs mediate anti-GBM therapeutic efficacy through the production of IFN-α, thus manipulation of pDCs constitutes an attractive new therapeutic target for the treatment of GBM. |
| first_indexed | 2024-12-18T19:20:17Z |
| format | Article |
| id | doaj.art-48055997b2cf415fbca0be0e9b4482d5 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-12-18T19:20:17Z |
| publishDate | 2012-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-48055997b2cf415fbca0be0e9b4482d52022-12-21T20:56:01ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022012-08-0114875777010.1593/neo.12794Plasmacytoid Dendritic Cells in the Tumor Microenvironment: Immune Targets for Glioma TherapeuticsMarianela Candolfi0Gwendalyn D. King1Kader Yagiz2James F. Curtin3Yohei Mineharu4AKM Ghulam Muhammad5David Foulad6Kurt M. Kroeger7Nick Barnett8Regis Josien9Pedro R. Lowenstein10Maria G. Castro11Gene Therapeutics Research Institute, Cedars Sinai Medical Center, and Departments of Molecular and Medical Pharmacology, and Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CAGene Therapeutics Research Institute, Cedars Sinai Medical Center, and Departments of Molecular and Medical Pharmacology, and Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CAGene Therapeutics Research Institute, Cedars Sinai Medical Center, and Departments of Molecular and Medical Pharmacology, and Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CAGene Therapeutics Research Institute, Cedars Sinai Medical Center, and Departments of Molecular and Medical Pharmacology, and Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CAGene Therapeutics Research Institute, Cedars Sinai Medical Center, and Departments of Molecular and Medical Pharmacology, and Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CAGene Therapeutics Research Institute, Cedars Sinai Medical Center, and Departments of Molecular and Medical Pharmacology, and Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CAGene Therapeutics Research Institute, Cedars Sinai Medical Center, and Departments of Molecular and Medical Pharmacology, and Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CAGene Therapeutics Research Institute, Cedars Sinai Medical Center, and Departments of Molecular and Medical Pharmacology, and Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CAGene Therapeutics Research Institute, Cedars Sinai Medical Center, and Departments of Molecular and Medical Pharmacology, and Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CAInstitut National de la Sante et de la Recherche Medicale (INSERM) U437 and ITERT, Nantes, FranceGene Therapeutics Research Institute, Cedars Sinai Medical Center, and Departments of Molecular and Medical Pharmacology, and Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CAGene Therapeutics Research Institute, Cedars Sinai Medical Center, and Departments of Molecular and Medical Pharmacology, and Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CAAdenovirus-mediated delivery of the immune-stimulatory cytokine Flt3L and the conditionally cytotoxic thymidine kinase (TK) induces tumor regression and long-term survival in preclinical glioma (glioblastoma multiforme [GBM]) models. Flt3L induces expansion and recruitment of plasmacytoid dendritic cells (pDCs) into the brain. Although pDCs can present antigen and produce powerful inflammatory cytokines, that is, interferon α (IFN-α), their role in tumor immunology remains debated. Thus, we studied the role of pDCs and IFN-α in Ad.TK/GCV+ Ad.Flt3L-mediated anti-GBM therapeutic efficacy. Our data indicate that the combined gene therapy induced recruitment of plasmacytoid DCs (pDCs) into the tumor mass; which were capable of in vivo phagocytosis, IFN-α release, and T-cell priming. Thus, we next used either pDCs or an Ad vector encoding IFN-α delivered within the tumor microenvironment. When rats were treated with Ad.TK/GCV in combination with pDCs or Ad-IFN-α, they exhibited 35% and 50% survival, respectively. However, whereas intracranial administration of Ad.TK/GCV + Ad.Flt3L exhibited a high safety profile, Ad-IFN-α led to severe local inflammation, with neurologic and systemic adverse effects. To elucidate whether the efficacy of the immunotherapy was dependent on IFN-α-secreting pDCs, we administered an Ad vector encoding B18R, an IFN-α antagonist, which abrogated the antitumoral effect of Ad.TK/GCV + Ad.Flt3L. Our data suggest that IFN-α release by activated pDCs plays a critical role in the antitumor effect mediated by Ad.TK/GCV + Ad.Flt3L. In summary, taken together, our results demonstrate that pDCs mediate anti-GBM therapeutic efficacy through the production of IFN-α, thus manipulation of pDCs constitutes an attractive new therapeutic target for the treatment of GBM.http://www.sciencedirect.com/science/article/pii/S1476558612800091 |
| spellingShingle | Marianela Candolfi Gwendalyn D. King Kader Yagiz James F. Curtin Yohei Mineharu AKM Ghulam Muhammad David Foulad Kurt M. Kroeger Nick Barnett Regis Josien Pedro R. Lowenstein Maria G. Castro Plasmacytoid Dendritic Cells in the Tumor Microenvironment: Immune Targets for Glioma Therapeutics Neoplasia: An International Journal for Oncology Research |
| title | Plasmacytoid Dendritic Cells in the Tumor Microenvironment: Immune Targets for Glioma Therapeutics |
| title_full | Plasmacytoid Dendritic Cells in the Tumor Microenvironment: Immune Targets for Glioma Therapeutics |
| title_fullStr | Plasmacytoid Dendritic Cells in the Tumor Microenvironment: Immune Targets for Glioma Therapeutics |
| title_full_unstemmed | Plasmacytoid Dendritic Cells in the Tumor Microenvironment: Immune Targets for Glioma Therapeutics |
| title_short | Plasmacytoid Dendritic Cells in the Tumor Microenvironment: Immune Targets for Glioma Therapeutics |
| title_sort | plasmacytoid dendritic cells in the tumor microenvironment immune targets for glioma therapeutics |
| url | http://www.sciencedirect.com/science/article/pii/S1476558612800091 |
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