Plasmacytoid Dendritic Cells In The Tumor Microenvironment: Immune Targets For Glioma Therapeutics

Authors
Candolfi, Marianela; King, Gwendalyn D.; Yagiz, Kader; Curtin, James F.; Mineharu, Yohei; Ghulam Muhammad, A.K.M.; Foulad, David; Kroeger, Kurt M.; Barnett, Nick; Josien, Regis; Lowenstein, Pedro R.; Castro, Maria Gabriela
Publication Year
2012
Language
English
Format
article
Status
Published version
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. © 2012 Neoplasia Press, Inc. All rights reserved.
Fil: Candolfi, Marianela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos
Fil: King, Gwendalyn D.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos
Fil: Yagiz, Kader. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos
Fil: Curtin, James F.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos
Fil: Mineharu, Yohei. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos
Fil: Ghulam Muhammad, A.K.M.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos
Fil: Foulad, David. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos
Fil: Kroeger, Kurt M.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos
Fil: Barnett, Nick. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos
Fil: Josien, Regis. Inserm; Francia
Fil: Lowenstein, Pedro R.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of Michigan; Estados Unidos
Fil: Castro, Maria Gabriela. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of Michigan; Estados Unidos
Subject
GLIOBLASTOMA
PLASMACYOTID DENDRITIC CELLS
GENE THERAPY
IFN-ALPHA
Otras Biotecnologías de la Salud
Biotecnología de la Salud
CIENCIAS MÉDICAS Y DE LA SALUD
Access level
Open access
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repository
CONICET Digital (CONICET)
Institution
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identifier
oai:ri.conicet.gov.ar:11336/67377