TY - JOUR
T1 - Plasmacytoid dendritic cells in the tumor microenvironment
T2 - Immune targets for glioma therapeutics
AU - Candolfi, Marianela
AU - King, Gwendalyn D.
AU - Yagiz, Kader
AU - Curtin, James F.
AU - Mineharu, Yohei
AU - Ghulam Muhammad, A. K.M.
AU - Foulad, David
AU - Kroeger, Kurt M.
AU - Barnett, Nick
AU - Josien, Regis
AU - Lowenstein, Pedro R.
AU - Castro, Maria G.
N1 - Funding Information:
Abbreviations: Ad, adenoviral vector; APC, antigen-presenting cell; DC, dendritic cell; dLN, draining lymph node; Flt3L, fms-like tyrosine kinase 3; GBM, glioblastoma multi-forme; IFN-α, interferon α; MHC, major histocompatibility complex; pDC, plasmacytoid dendritic cell; TK, thymidine kinase; TLR, Toll-like receptor Address all correspondence to: Maria G. Castro, PhD, Department of Neurosurgery, Department of Cell and Developmental Biology, University of Michigan School of Medicine, 4570 MSRB II, 1150 W Medical Center Dr, Ann Arbor, MI 48109-5689. E-mail: mariacas@umich.edu 1Our work was supported by National Institutes of Health/National Institute of Neurological Disorders & Stroke (NIH/NINDS) grants 1UO1 NS052465, UO1-NS052465-04S1, 1RO1-NS057711, and 1RO1-NS074387 to M.G.C.; NIH/NINDS grants 1RO1-NS 054193; and 1RO1-NS061107 to P.R.L.; The Bram and Elaine Goldsmith and the Medallions Group Endowed Chairs in Gene Therapeutics to P.R.L. and M.G.C., respectively, the Board of Governors at CSMC and the Department of Neurosurgery, University of Michigan School of Medicine. M.C. was supported by an NIH/NINDS 1F32 NS058156 fellowship and the National Council of Science and Technology (CONICET, Argentina). 2This article refers to supplementary materials, which are designated by Figures W1 to W5 and are available online at www.neoplasia.com. 3Current address: Instituto de Investigaciones Biomédicas, INBIOMED, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, piso 10, CP 1421 Buenos Aires, Argentina. 4Deceased. Received 8 May 2012; Revised 10 July 2012; Accepted 11 July 2012 Copyright © 2012 Neoplasia Press, Inc. All rights reserved 1522-8002/12/$25.00 DOI 10.1593/neo.12794
PY - 2012/8
Y1 - 2012/8
N2 - 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.
AB - 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.
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U2 - 10.1593/neo.12794
DO - 10.1593/neo.12794
M3 - Article
C2 - 22952428
AN - SCOPUS:84865268850
VL - 14
SP - 757
EP - 770
JO - Neoplasia
JF - Neoplasia
SN - 1522-8002
IS - 8
ER -