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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/67377
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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 Técnicas2025-09-03T09:57:15Zoai: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:34982025-09-03 09:57:16.191CONICET 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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1842269452282888192 |
score |
13.13397 |