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Plasmacytoid Dendritic Cells in the Tumor Microenvironment: Immune Targets for Glioma Therapeutics

Candolfi, Marianela ; King, Gwendalyn D ; Yagiz, Kader ; Curtin, James F ; Mineharu, Yohei ; Muhammad, AKM Ghulam ; Foulad, David ; Kroeger, Kurt M ; Barnett, Nick ; Josien, Regis ; Lowenstein, Pedro R ; Castro, Maria G

Neoplasia (New York, N.Y.), 2012-08, Vol.14 (8), p.757-IN26 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
Plasmacytoid Dendritic Cells in the Tumor Microenvironment: Immune Targets for Glioma Therapeutics
Autor: Candolfi, Marianela ; King, Gwendalyn D ; Yagiz, Kader ; Curtin, James F ; Mineharu, Yohei ; Muhammad, AKM Ghulam ; Foulad, David ; Kroeger, Kurt M ; Barnett, Nick ; Josien, Regis ; Lowenstein, Pedro R ; Castro, Maria G
Assuntos: Adenoviridae - genetics ; Animals ; Brain Neoplasms - immunology ; Brain Neoplasms - pathology ; Brain Neoplasms - therapy ; Dendritic Cells - immunology ; Genetic Therapy ; Glioblastoma - immunology ; Glioblastoma - pathology ; Glioblastoma - therapy ; Immunotherapy ; Interferon-alpha - immunology ; Lymphocyte Activation ; Lymphocyte Culture Test, Mixed ; Lymphocytes, Tumor-Infiltrating - immunology ; Membrane Proteins - genetics ; Oncology ; Rats ; T-Lymphocytes - immunology ; Thymidine Kinase - genetics ; Tumor Microenvironment
É parte de: Neoplasia (New York, N.Y.), 2012-08, Vol.14 (8), p.757-IN26
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Descrição: Abstract 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.
Editor: United States: Elsevier Inc
Idioma: Inglês

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Plasmacytoid Dendritic Cells in the Tumor Microenvironment: Immune Targets for Glioma Therapeutics

Candolfi, Marianela ; King, Gwendalyn D ; Yagiz, Kader ; Curtin, James F ; Mineharu, Yohei ; Muhammad, AKM Ghulam ; Foulad, David ; Kroeger, Kurt M ; Barnett, Nick ; Josien, Regis ; Lowenstein, Pedro R ; Castro, Maria G

United States: Elsevier Inc

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