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

Autores
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
Año de publicación
2012
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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
Materia
GLIOBLASTOMA
PLASMACYOTID DENDRITIC CELLS
GENE THERAPY
IFN-ALPHA
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/67377
Acceder
id CONICETDig_0083bc0e9de0ce6504f6636e87c9835c
oai_identifier_str oai:ri.conicet.gov.ar:11336/67377
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Plasmacytoid Dendritic Cells In The Tumor Microenvironment: Immune Targets For Glioma TherapeuticsCandolfi, MarianelaKing, Gwendalyn D.Yagiz, KaderCurtin, James F.Mineharu, YoheiGhulam Muhammad, A.K.M.Foulad, DavidKroeger, Kurt M.Barnett, NickJosien, RegisLowenstein, Pedro R.Castro, Maria GabrielaGLIOBLASTOMAPLASMACYOTID DENDRITIC CELLSGENE THERAPYIFN-ALPHAhttps://purl.org/becyt/ford/3.4https://purl.org/becyt/ford/3Adenovirus-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 UnidosFil: King, Gwendalyn D.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados UnidosFil: Yagiz, Kader. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados UnidosFil: Curtin, James F.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados UnidosFil: Mineharu, Yohei. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados UnidosFil: Ghulam Muhammad, A.K.M.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados UnidosFil: Foulad, David. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados UnidosFil: Kroeger, Kurt M.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados UnidosFil: Barnett, Nick. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados UnidosFil: Josien, Regis. Inserm; FranciaFil: Lowenstein, Pedro R.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of Michigan; Estados UnidosFil: Castro, Maria Gabriela. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of Michigan; Estados UnidosNeoplasia Press2012-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/67377Candolfi, Marianela; King, Gwendalyn D.; Yagiz, Kader; Curtin, James F.; Mineharu, Yohei; et al.; Plasmacytoid Dendritic Cells In The Tumor Microenvironment: Immune Targets For Glioma Therapeutics; Neoplasia Press; Neoplasia; 14; 8; 8-2012; 757-7701522-8002CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1593/neo.12794info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S1476558612800091info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:02:55Zoai:ri.conicet.gov.ar:11336/67377instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:02:55.783CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Plasmacytoid Dendritic Cells In The Tumor Microenvironment: Immune Targets For Glioma Therapeutics
title Plasmacytoid Dendritic Cells In The Tumor Microenvironment: Immune Targets For Glioma Therapeutics
spellingShingle Plasmacytoid Dendritic Cells In The Tumor Microenvironment: Immune Targets For Glioma Therapeutics
Candolfi, Marianela
GLIOBLASTOMA
PLASMACYOTID DENDRITIC CELLS
GENE THERAPY
IFN-ALPHA
title_short Plasmacytoid Dendritic Cells In The Tumor Microenvironment: Immune Targets For Glioma Therapeutics
title_full Plasmacytoid Dendritic Cells In The Tumor Microenvironment: Immune Targets For Glioma Therapeutics
title_fullStr Plasmacytoid Dendritic Cells In The Tumor Microenvironment: Immune Targets For Glioma Therapeutics
title_full_unstemmed Plasmacytoid Dendritic Cells In The Tumor Microenvironment: Immune Targets For Glioma Therapeutics
title_sort Plasmacytoid Dendritic Cells In The Tumor Microenvironment: Immune Targets For Glioma Therapeutics
dc.creator.none.fl_str_mv 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
author Candolfi, Marianela
author_facet 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
author_role author
author2 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
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv GLIOBLASTOMA
PLASMACYOTID DENDRITIC CELLS
GENE THERAPY
IFN-ALPHA
topic GLIOBLASTOMA
PLASMACYOTID DENDRITIC CELLS
GENE THERAPY
IFN-ALPHA
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.4
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv 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
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.
publishDate 2012
dc.date.none.fl_str_mv 2012-08
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/67377
Candolfi, Marianela; King, Gwendalyn D.; Yagiz, Kader; Curtin, James F.; Mineharu, Yohei; et al.; Plasmacytoid Dendritic Cells In The Tumor Microenvironment: Immune Targets For Glioma Therapeutics; Neoplasia Press; Neoplasia; 14; 8; 8-2012; 757-770
1522-8002
CONICET Digital
CONICET
url http://hdl.handle.net/11336/67377
identifier_str_mv Candolfi, Marianela; King, Gwendalyn D.; Yagiz, Kader; Curtin, James F.; Mineharu, Yohei; et al.; Plasmacytoid Dendritic Cells In The Tumor Microenvironment: Immune Targets For Glioma Therapeutics; Neoplasia Press; Neoplasia; 14; 8; 8-2012; 757-770
1522-8002
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1593/neo.12794
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S1476558612800091
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Neoplasia Press
publisher.none.fl_str_mv Neoplasia Press
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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