Targeting TMEM176B enhances antitumor immunity and augments the efficacy of immune checkpoint blockers by unleashing inflammasome activation

Autores
Segovia, Mercedes; Russo, Sofia; Jeldres, Mathias; Mahmoud, Yamil Damián; Perez, Valentina; Duhalde, Maite; Charnet, Pierre; Rousset, Matthieu; Victoria, Sabina; Veigas, Florenci; Louvet, Cédric; Vanhove, Bernard; Floto, R. Andrés; Anegon, Ignacio; Cuturi, Maria Cristina; Girotti, Maria Romina; Rabinovich, Gabriel Adrián; Hill, Marcelo
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Although immune checkpoint blockers have yielded significant clinical benefits in patients with different malignancies, the efficacy of these therapies is still limited. Here, we show that disruption of transmembrane protein 176B (TMEM176B)contributes to CD8 + T cell-mediated tumor growth inhibition by unleashing inflammasome activation. Lack of Tmem176b enhances the antitumor activity of anti-CTLA-4 antibodies through mechanisms involving caspase-1/IL-1β activation. Accordingly, patients responding to checkpoint blockade therapies display an activated inflammasome signature. Finally, we identify BayK8644 as a potent TMEM176B inhibitor that promotes CD8 + T cell-mediated tumor control and reinforces the antitumor activity of both anti-CTLA-4 and anti-PD-1 antibodies. Thus, pharmacologic de-repression of the inflammasome by targeting TMEM176B may enhance the therapeutic efficacy of immune checkpoint blockers.
Fil: Segovia, Mercedes. Instituto Pasteur de Montevideo; Uruguay. Universidad de la Republica. Facultad de Medicina.; Uruguay
Fil: Russo, Sofia. Universidad de la Republica. Facultad de Medicina.; Uruguay. Instituto Pasteur de Montevideo; Uruguay
Fil: Jeldres, Mathias. Instituto Pasteur de Montevideo; Uruguay
Fil: Mahmoud, Yamil Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Perez, Valentina. Universidad de la Republica. Facultad de Medicina.; Uruguay. Instituto Pasteur de Montevideo; Uruguay
Fil: Duhalde, Maite. Instituto Pasteur de Montevideo; Uruguay
Fil: Charnet, Pierre. Univeristé de Montpellier; Francia
Fil: Rousset, Matthieu. Univeristé de Montpellier; Francia
Fil: Victoria, Sabina. Instituto Pasteur de Montevideo; Uruguay
Fil: Veigas, Florenci. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Louvet, Cédric. Inserm; Francia
Fil: Vanhove, Bernard. XENOTHERA; Francia. Inserm; Francia
Fil: Floto, R. Andrés. University of Cambridge; Estados Unidos
Fil: Anegon, Ignacio. Inserm; Francia
Fil: Cuturi, Maria Cristina. Inserm; Francia
Fil: Girotti, Maria Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
Fil: Hill, Marcelo. Instituto Pasteur de Montevideo; Uruguay. Universidad de la Republica. Facultad de Medicina.; Uruguay
Materia
CANCER
DENDRITIC CELLS
IMMUNE CHECKPOINT BLOCKERS
INFLAMMASOME
ION CHANNEL
TMEM176B
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:11336/104725
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/104725
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Targeting TMEM176B enhances antitumor immunity and augments the efficacy of immune checkpoint blockers by unleashing inflammasome activationSegovia, MercedesRusso, SofiaJeldres, MathiasMahmoud, Yamil DamiánPerez, ValentinaDuhalde, MaiteCharnet, PierreRousset, MatthieuVictoria, SabinaVeigas, FlorenciLouvet, CédricVanhove, BernardFloto, R. AndrésAnegon, IgnacioCuturi, Maria CristinaGirotti, Maria RominaRabinovich, Gabriel AdriánHill, MarceloCANCERDENDRITIC CELLSIMMUNE CHECKPOINT BLOCKERSINFLAMMASOMEION CHANNELTMEM176Bhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1https://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Although immune checkpoint blockers have yielded significant clinical benefits in patients with different malignancies, the efficacy of these therapies is still limited. Here, we show that disruption of transmembrane protein 176B (TMEM176B)contributes to CD8 + T cell-mediated tumor growth inhibition by unleashing inflammasome activation. Lack of Tmem176b enhances the antitumor activity of anti-CTLA-4 antibodies through mechanisms involving caspase-1/IL-1β activation. Accordingly, patients responding to checkpoint blockade therapies display an activated inflammasome signature. Finally, we identify BayK8644 as a potent TMEM176B inhibitor that promotes CD8 + T cell-mediated tumor control and reinforces the antitumor activity of both anti-CTLA-4 and anti-PD-1 antibodies. Thus, pharmacologic de-repression of the inflammasome by targeting TMEM176B may enhance the therapeutic efficacy of immune checkpoint blockers.Fil: Segovia, Mercedes. Instituto Pasteur de Montevideo; Uruguay. Universidad de la Republica. Facultad de Medicina.; UruguayFil: Russo, Sofia. Universidad de la Republica. Facultad de Medicina.; Uruguay. Instituto Pasteur de Montevideo; UruguayFil: Jeldres, Mathias. Instituto Pasteur de Montevideo; UruguayFil: Mahmoud, Yamil Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Perez, Valentina. Universidad de la Republica. Facultad de Medicina.; Uruguay. Instituto Pasteur de Montevideo; UruguayFil: Duhalde, Maite. Instituto Pasteur de Montevideo; UruguayFil: Charnet, Pierre. Univeristé de Montpellier; FranciaFil: Rousset, Matthieu. Univeristé de Montpellier; FranciaFil: Victoria, Sabina. Instituto Pasteur de Montevideo; UruguayFil: Veigas, Florenci. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Louvet, Cédric. Inserm; FranciaFil: Vanhove, Bernard. XENOTHERA; Francia. Inserm; FranciaFil: Floto, R. Andrés. University of Cambridge; Estados UnidosFil: Anegon, Ignacio. Inserm; FranciaFil: Cuturi, Maria Cristina. Inserm; FranciaFil: Girotti, Maria Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Hill, Marcelo. Instituto Pasteur de Montevideo; Uruguay. Universidad de la Republica. Facultad de Medicina.; UruguayCell Press2019-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/104725Segovia, Mercedes; Russo, Sofia; Jeldres, Mathias; Mahmoud, Yamil Damián; Perez, Valentina; et al.; Targeting TMEM176B enhances antitumor immunity and augments the efficacy of immune checkpoint blockers by unleashing inflammasome activation; Cell Press; Cancer Cell; 35; 5; 5-2019; 767-7811535-6108CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S1535610819301989info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ccell.2019.04.003info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:59:27Zoai:ri.conicet.gov.ar:11336/104725instacron: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 09:59:27.881CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Targeting TMEM176B enhances antitumor immunity and augments the efficacy of immune checkpoint blockers by unleashing inflammasome activation
title Targeting TMEM176B enhances antitumor immunity and augments the efficacy of immune checkpoint blockers by unleashing inflammasome activation
spellingShingle Targeting TMEM176B enhances antitumor immunity and augments the efficacy of immune checkpoint blockers by unleashing inflammasome activation
Segovia, Mercedes
CANCER
DENDRITIC CELLS
IMMUNE CHECKPOINT BLOCKERS
INFLAMMASOME
ION CHANNEL
TMEM176B
title_short Targeting TMEM176B enhances antitumor immunity and augments the efficacy of immune checkpoint blockers by unleashing inflammasome activation
title_full Targeting TMEM176B enhances antitumor immunity and augments the efficacy of immune checkpoint blockers by unleashing inflammasome activation
title_fullStr Targeting TMEM176B enhances antitumor immunity and augments the efficacy of immune checkpoint blockers by unleashing inflammasome activation
title_full_unstemmed Targeting TMEM176B enhances antitumor immunity and augments the efficacy of immune checkpoint blockers by unleashing inflammasome activation
title_sort Targeting TMEM176B enhances antitumor immunity and augments the efficacy of immune checkpoint blockers by unleashing inflammasome activation
dc.creator.none.fl_str_mv Segovia, Mercedes
Russo, Sofia
Jeldres, Mathias
Mahmoud, Yamil Damián
Perez, Valentina
Duhalde, Maite
Charnet, Pierre
Rousset, Matthieu
Victoria, Sabina
Veigas, Florenci
Louvet, Cédric
Vanhove, Bernard
Floto, R. Andrés
Anegon, Ignacio
Cuturi, Maria Cristina
Girotti, Maria Romina
Rabinovich, Gabriel Adrián
Hill, Marcelo
author Segovia, Mercedes
author_facet Segovia, Mercedes
Russo, Sofia
Jeldres, Mathias
Mahmoud, Yamil Damián
Perez, Valentina
Duhalde, Maite
Charnet, Pierre
Rousset, Matthieu
Victoria, Sabina
Veigas, Florenci
Louvet, Cédric
Vanhove, Bernard
Floto, R. Andrés
Anegon, Ignacio
Cuturi, Maria Cristina
Girotti, Maria Romina
Rabinovich, Gabriel Adrián
Hill, Marcelo
author_role author
author2 Russo, Sofia
Jeldres, Mathias
Mahmoud, Yamil Damián
Perez, Valentina
Duhalde, Maite
Charnet, Pierre
Rousset, Matthieu
Victoria, Sabina
Veigas, Florenci
Louvet, Cédric
Vanhove, Bernard
Floto, R. Andrés
Anegon, Ignacio
Cuturi, Maria Cristina
Girotti, Maria Romina
Rabinovich, Gabriel Adrián
Hill, Marcelo
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv CANCER
DENDRITIC CELLS
IMMUNE CHECKPOINT BLOCKERS
INFLAMMASOME
ION CHANNEL
TMEM176B
topic CANCER
DENDRITIC CELLS
IMMUNE CHECKPOINT BLOCKERS
INFLAMMASOME
ION CHANNEL
TMEM176B
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Although immune checkpoint blockers have yielded significant clinical benefits in patients with different malignancies, the efficacy of these therapies is still limited. Here, we show that disruption of transmembrane protein 176B (TMEM176B)contributes to CD8 + T cell-mediated tumor growth inhibition by unleashing inflammasome activation. Lack of Tmem176b enhances the antitumor activity of anti-CTLA-4 antibodies through mechanisms involving caspase-1/IL-1β activation. Accordingly, patients responding to checkpoint blockade therapies display an activated inflammasome signature. Finally, we identify BayK8644 as a potent TMEM176B inhibitor that promotes CD8 + T cell-mediated tumor control and reinforces the antitumor activity of both anti-CTLA-4 and anti-PD-1 antibodies. Thus, pharmacologic de-repression of the inflammasome by targeting TMEM176B may enhance the therapeutic efficacy of immune checkpoint blockers.
Fil: Segovia, Mercedes. Instituto Pasteur de Montevideo; Uruguay. Universidad de la Republica. Facultad de Medicina.; Uruguay
Fil: Russo, Sofia. Universidad de la Republica. Facultad de Medicina.; Uruguay. Instituto Pasteur de Montevideo; Uruguay
Fil: Jeldres, Mathias. Instituto Pasteur de Montevideo; Uruguay
Fil: Mahmoud, Yamil Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Perez, Valentina. Universidad de la Republica. Facultad de Medicina.; Uruguay. Instituto Pasteur de Montevideo; Uruguay
Fil: Duhalde, Maite. Instituto Pasteur de Montevideo; Uruguay
Fil: Charnet, Pierre. Univeristé de Montpellier; Francia
Fil: Rousset, Matthieu. Univeristé de Montpellier; Francia
Fil: Victoria, Sabina. Instituto Pasteur de Montevideo; Uruguay
Fil: Veigas, Florenci. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Louvet, Cédric. Inserm; Francia
Fil: Vanhove, Bernard. XENOTHERA; Francia. Inserm; Francia
Fil: Floto, R. Andrés. University of Cambridge; Estados Unidos
Fil: Anegon, Ignacio. Inserm; Francia
Fil: Cuturi, Maria Cristina. Inserm; Francia
Fil: Girotti, Maria Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
Fil: Hill, Marcelo. Instituto Pasteur de Montevideo; Uruguay. Universidad de la Republica. Facultad de Medicina.; Uruguay
description Although immune checkpoint blockers have yielded significant clinical benefits in patients with different malignancies, the efficacy of these therapies is still limited. Here, we show that disruption of transmembrane protein 176B (TMEM176B)contributes to CD8 + T cell-mediated tumor growth inhibition by unleashing inflammasome activation. Lack of Tmem176b enhances the antitumor activity of anti-CTLA-4 antibodies through mechanisms involving caspase-1/IL-1β activation. Accordingly, patients responding to checkpoint blockade therapies display an activated inflammasome signature. Finally, we identify BayK8644 as a potent TMEM176B inhibitor that promotes CD8 + T cell-mediated tumor control and reinforces the antitumor activity of both anti-CTLA-4 and anti-PD-1 antibodies. Thus, pharmacologic de-repression of the inflammasome by targeting TMEM176B may enhance the therapeutic efficacy of immune checkpoint blockers.
publishDate 2019
dc.date.none.fl_str_mv 2019-05
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/11336/104725
Segovia, Mercedes; Russo, Sofia; Jeldres, Mathias; Mahmoud, Yamil Damián; Perez, Valentina; et al.; Targeting TMEM176B enhances antitumor immunity and augments the efficacy of immune checkpoint blockers by unleashing inflammasome activation; Cell Press; Cancer Cell; 35; 5; 5-2019; 767-781
1535-6108
CONICET Digital
CONICET
url http://hdl.handle.net/11336/104725
identifier_str_mv Segovia, Mercedes; Russo, Sofia; Jeldres, Mathias; Mahmoud, Yamil Damián; Perez, Valentina; et al.; Targeting TMEM176B enhances antitumor immunity and augments the efficacy of immune checkpoint blockers by unleashing inflammasome activation; Cell Press; Cancer Cell; 35; 5; 5-2019; 767-781
1535-6108
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S1535610819301989
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ccell.2019.04.003
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
application/pdf
dc.publisher.none.fl_str_mv Cell Press
publisher.none.fl_str_mv Cell 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 13.13397

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