title: Plasmacytoid dendritic cells in the tumor microenvironment: immune targets for glioma therapeutics.
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.
authors.affiliation: Gene Therapeutics Research Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Marianela
authors.initials: M
authors.lastname: Candolfi
authors.forename: Gwendalyn D
authors.initials: GD
authors.lastname: King
authors.forename: Kader
authors.initials: K
authors.lastname: Yagiz
authors.forename: James F
authors.initials: JF
authors.lastname: Curtin
authors.forename: Yohei
authors.initials: Y
authors.lastname: Mineharu
authors.forename: A K M Ghulam
authors.initials: AK
authors.lastname: Muhammad
authors.forename: David
authors.initials: D
authors.lastname: Foulad
authors.forename: Kurt M
authors.initials: KM
authors.lastname: Kroeger
authors.forename: Nick
authors.initials: N
authors.lastname: Barnett
authors.forename: Regis
authors.initials: R
authors.lastname: Josien
authors.forename: Pedro R
authors.initials: PR
authors.lastname: Lowenstein
authors.forename: Maria G
authors.initials: MG
authors.lastname: Castro
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D003713:Dendritic Cells / Q000276:immunology*; D015316:Genetic Therapy; D005909:Glioblastoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D007167:Immunotherapy; D016898:Interferon-alpha / Q000276:immunology*; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics; D051381:Rats; D013601:T-Lymphocytes / Q000276:immunology; D013937:Thymidine Kinase / Q000235:genetics; D059016:Tumor Microenvironment
chemical_list: D016898:Interferon-alpha; D008565:Membrane Proteins; C084881:flt3 ligand protein; D013937:Thymidine Kinase