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 ? (IFN-?), their role in tumor immunology remains debated. Thus, we studied the role of pDCs and IFN-? 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-? release, and T-cell priming. Thus, we next used either pDCs or an Ad vector encoding IFN-? delivered within the tumor microenvironment. When rats were treated with Ad.TK/GCV in combination with pDCs or Ad-IFN-?, they exhibited 35% and 50% survival, respectively. However, whereas intracranial administration of Ad.TK/GCV + Ad.Flt3L exhibited a high safety profile, Ad-IFN-? led to severe local inflammation, with neurologic and systemic adverse effects. To elucidate whether the efficacy of the immunotherapy was dependent on IFN-?-secreting pDCs, we administered an Ad vector encoding B18R, an IFN-? antagonist, which abrogated the antitumoral effect of Ad.TK/GCV + Ad.Flt3L. Our data suggest that IFN-? 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-?, thus manipulation of pDCs constitutes an attractive new therapeutic target for the treatment of GBM.

SUBMITTER: Candolfi M 

PROVIDER: S-EPMC3431182 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature