Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells

Sánchez-Paulete, Alfonso R; Cueto, Francisco J.; Martínez-López, María; Labiano, Sara; Morales-Kastresana, Aizea; Rodríguez-Ruiz, María E; Jure-Kunkel, Maria; Azpilikueta, Arantza; Aznar, M Angela; Quetglas, José I; Sancho, David; Melero, Ignacio

Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells

UNLABELLED: Weak and ineffective antitumor cytotoxic T lymphocyte (CTL) responses can be rescued by immunomodulatory mAbs targeting PD-1 or CD137. Using Batf3(-/-) mice, which are defective for cross-presentation of cell-associated antigens, we show that BATF3-dependent dendritic cells (DC) are esse...

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Autores:	Sánchez-Paulete, Alfonso R, Cueto, Francisco J., Martínez-López, María, Labiano, Sara, Morales-Kastresana, Aizea, Rodríguez-Ruiz, María E, Jure-Kunkel, Maria, Azpilikueta, Arantza, Aznar, M Angela, Quetglas, José I, Sancho, David, Melero, Ignacio
Tipo de recurso:	artículo
Fecha de publicación:	2016
País:	España
Institución:	Instituto de Salud Carlos III (ISCIII)
Repositorio:	Repisalud
Idioma:	inglés
OAI Identifier:	oai:repisalud.isciii.es:20.500.12105/9721
Acceso en línea:	http://hdl.handle.net/20.500.12105/9721
Access Level:	acceso abierto
Palabra clave:	Animals Antibodies, Monoclonal Basic-Leucine Zipper Transcription Factors Cell Line, Tumor Dendritic Cells Humans Immunotherapy Lymphocyte Activation Melanoma, Experimental Mice Mice, Transgenic Programmed Cell Death 1 Receptor Repressor Proteins Tumor Necrosis Factor Receptor Superfamily, Member 9

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spelling	Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic CellsSánchez-Paulete, Alfonso RCueto, Francisco J.Martínez-López, MaríaLabiano, SaraMorales-Kastresana, AizeaRodríguez-Ruiz, María EJure-Kunkel, MariaAzpilikueta, ArantzaAznar, M AngelaQuetglas, José ISancho, DavidMelero, IgnacioAnimalsAntibodies, MonoclonalBasic-Leucine Zipper Transcription FactorsCell Line, TumorDendritic CellsHumansImmunotherapyLymphocyte ActivationMelanoma, ExperimentalMiceMice, TransgenicProgrammed Cell Death 1 ReceptorRepressor ProteinsTumor Necrosis Factor Receptor Superfamily, Member 9UNLABELLED: Weak and ineffective antitumor cytotoxic T lymphocyte (CTL) responses can be rescued by immunomodulatory mAbs targeting PD-1 or CD137. Using Batf3(-/-) mice, which are defective for cross-presentation of cell-associated antigens, we show that BATF3-dependent dendritic cells (DC) are essential for the response to therapy with anti-CD137 or anti-PD-1 mAbs. Batf3(-/-) mice failed to prime an endogenous CTL-mediated immune response toward tumor-associated antigens, including neoantigens. As a result, the immunomodulatory mAbs could not amplify any therapeutically functional immune response in these mice. Moreover, administration of systemic sFLT3L and local poly-ICLC enhanced DC-mediated cross-priming and synergized with anti-CD137- and anti-PD-1-mediated immunostimulation in tumor therapy against B16-ovalbumin-derived melanomas, whereas this function was lost in Batf3(-/-) mice. These experiments show that cross-priming of tumor antigens by FLT3L- and BATF3-dependent DCs is crucial to the efficacy of immunostimulatory mAbs and represents a very attractive point of intervention to enhance their clinical antitumor effects. SIGNIFICANCE: Immunotherapy with immunostimulatory mAbs is currently achieving durable clinical responses in different types of cancer. We show that cross-priming of tumor antigens by BATF3-dependent DCs is a key limiting factor that can be exploited to enhance the antitumor efficacy of anti-PD-1 and anti-CD137 immunostimulatory mAbs.American Association for Cancer Research (AACR)Ministerio de Ciencia e Innovación (España)Gobierno de Navarra (España)Unión Europea. Comisión EuropeaMinisterio de Economía y Competitividad (España)Fundación ProCNIC20202020-04-2320162016-01-0120162016-01-01journal articlehttp://purl.org/coar/resource_type/c_6501AMhttp://purl.org/coar/version/c_ab4af688f83e57aainfo:eu-repo/semantics/articleapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/20.500.12105/9721reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengEuropean Commission http://dx.doi.org/10.13039/501100000780 Horizon 2020 Framework Programme 635122open accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/97212026-06-12T12:43:37Z
dc.title.none.fl_str_mv	Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells
title	Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells
spellingShingle	Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells Sánchez-Paulete, Alfonso R Animals Antibodies, Monoclonal Basic-Leucine Zipper Transcription Factors Cell Line, Tumor Dendritic Cells Humans Immunotherapy Lymphocyte Activation Melanoma, Experimental Mice Mice, Transgenic Programmed Cell Death 1 Receptor Repressor Proteins Tumor Necrosis Factor Receptor Superfamily, Member 9
title_short	Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells
title_full	Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells
title_fullStr	Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells
title_full_unstemmed	Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells
title_sort	Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells
dc.creator.none.fl_str_mv	Sánchez-Paulete, Alfonso R Cueto, Francisco J. Martínez-López, María Labiano, Sara Morales-Kastresana, Aizea Rodríguez-Ruiz, María E Jure-Kunkel, Maria Azpilikueta, Arantza Aznar, M Angela Quetglas, José I Sancho, David Melero, Ignacio
author	Sánchez-Paulete, Alfonso R
author_facet	Sánchez-Paulete, Alfonso R Cueto, Francisco J. Martínez-López, María Labiano, Sara Morales-Kastresana, Aizea Rodríguez-Ruiz, María E Jure-Kunkel, Maria Azpilikueta, Arantza Aznar, M Angela Quetglas, José I Sancho, David Melero, Ignacio
author_role	author
author2	Cueto, Francisco J. Martínez-López, María Labiano, Sara Morales-Kastresana, Aizea Rodríguez-Ruiz, María E Jure-Kunkel, Maria Azpilikueta, Arantza Aznar, M Angela Quetglas, José I Sancho, David Melero, Ignacio
author2_role	author author author author author author author author author author author
dc.contributor.none.fl_str_mv	Ministerio de Ciencia e Innovación (España) Gobierno de Navarra (España) Unión Europea. Comisión Europea Ministerio de Economía y Competitividad (España) Fundación ProCNIC
dc.subject.none.fl_str_mv	Animals Antibodies, Monoclonal Basic-Leucine Zipper Transcription Factors Cell Line, Tumor Dendritic Cells Humans Immunotherapy Lymphocyte Activation Melanoma, Experimental Mice Mice, Transgenic Programmed Cell Death 1 Receptor Repressor Proteins Tumor Necrosis Factor Receptor Superfamily, Member 9
topic	Animals Antibodies, Monoclonal Basic-Leucine Zipper Transcription Factors Cell Line, Tumor Dendritic Cells Humans Immunotherapy Lymphocyte Activation Melanoma, Experimental Mice Mice, Transgenic Programmed Cell Death 1 Receptor Repressor Proteins Tumor Necrosis Factor Receptor Superfamily, Member 9
description	UNLABELLED: Weak and ineffective antitumor cytotoxic T lymphocyte (CTL) responses can be rescued by immunomodulatory mAbs targeting PD-1 or CD137. Using Batf3(-/-) mice, which are defective for cross-presentation of cell-associated antigens, we show that BATF3-dependent dendritic cells (DC) are essential for the response to therapy with anti-CD137 or anti-PD-1 mAbs. Batf3(-/-) mice failed to prime an endogenous CTL-mediated immune response toward tumor-associated antigens, including neoantigens. As a result, the immunomodulatory mAbs could not amplify any therapeutically functional immune response in these mice. Moreover, administration of systemic sFLT3L and local poly-ICLC enhanced DC-mediated cross-priming and synergized with anti-CD137- and anti-PD-1-mediated immunostimulation in tumor therapy against B16-ovalbumin-derived melanomas, whereas this function was lost in Batf3(-/-) mice. These experiments show that cross-priming of tumor antigens by FLT3L- and BATF3-dependent DCs is crucial to the efficacy of immunostimulatory mAbs and represents a very attractive point of intervention to enhance their clinical antitumor effects. SIGNIFICANCE: Immunotherapy with immunostimulatory mAbs is currently achieving durable clinical responses in different types of cancer. We show that cross-priming of tumor antigens by BATF3-dependent DCs is a key limiting factor that can be exploited to enhance the antitumor efficacy of anti-PD-1 and anti-CD137 immunostimulatory mAbs.
publishDate	2016
dc.date.none.fl_str_mv	2016 2016-01-01 2016 2016-01-01 2020 2020-04-23
dc.type.none.fl_str_mv	journal article http://purl.org/coar/resource_type/c_6501 AM http://purl.org/coar/version/c_ab4af688f83e57aa
dc.type.openaire.fl_str_mv	info:eu-repo/semantics/article
format	article
dc.identifier.none.fl_str_mv	http://hdl.handle.net/20.500.12105/9721
url	http://hdl.handle.net/20.500.12105/9721
dc.language.none.fl_str_mv	Inglés eng
language_invalid_str_mv	Inglés
language	eng
dc.relation.none.fl_str_mv	European Commission http://dx.doi.org/10.13039/501100000780 Horizon 2020 Framework Programme 635122
dc.rights.none.fl_str_mv	open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 Internacional http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv	info:eu-repo/semantics/openAccess
rights_invalid_str_mv	open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 Internacional http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf application/pdf application/pdf application/pdf application/pdf application/pdf
dc.publisher.none.fl_str_mv	American Association for Cancer Research (AACR)
publisher.none.fl_str_mv	American Association for Cancer Research (AACR)
dc.source.none.fl_str_mv	reponame:Repisalud instname:Instituto de Salud Carlos III (ISCIII)
instname_str	Instituto de Salud Carlos III (ISCIII)
reponame_str	Repisalud
collection	Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score	15,81155

Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells

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