Overexpression of CD85j in TNBC patients inhibits Cetuximab-mediated NK-cell ADCC but can be restored with CD85j functional blockade

Autores
Roberti, María Paula; Juliá, Estefanía Paula; Rocca, Yamila; Amat, Mora; Bravo, Alicia Inés; Loza, José; Coló, Federico; Loza, Carlos Martín; Fabiano, Verónica; Maino, Merecedes; Podhorzer, Ariel; Fainboim, Leonardo; Barrio, Maria Marcela; Mordoh, Jose; Levy, Estrella Mariel
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Clinical studies suggest that triple negative breast cancer (TNBC) patients with epidermal growth factor receptor (EGFR)-expressing tumors could benefit from therapy with Cetuximab, which targets EGFR. NK cells are the primary effectors of antibody (Ab)-dependent cell-mediated cytotoxicity (ADCC) and thus play a role in Ab-based therapies. We have previously described diminished levels of Cetuximab-mediated ADCC in vitro in patients with advanced breast cancer. Here, we investigated the potential causes of this NK-cell functional deficiency. We characterized NK-cell activating/inhibitory receptors in the peripheral blood of breast cancer patients and found CD85j inhibitory receptor overexpression. The capacity of NK cells to perform Cetuximab-triggered ADCC against TNBC cells correlated inversely with CD85j expression, even in the presence of the stimulatory cytokines IL-2 or IL-15. Hence, patients expressing high levels of CD85j had an impaired ability to lyse TNBC cells in the presence of Cetuximab. We also found that CD85j overexpression was associated with HLA-I and soluble HLA-G expression by tumors. A CD85j functional blockade with a CD85j antagonist Ab restored ADCC levels in breast cancer patients and reverted this negative effect. Our data suggest that strategies that overcome the hurdles of immune activation could improve Cetuximab clinical efficacy.
Fil: Roberti, María Paula. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina
Fil: Juliá, Estefanía Paula. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Rocca, Yamila. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Amat, Mora. Instituto Alexander Fleming; Argentina
Fil: Bravo, Alicia Inés. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; Argentina
Fil: Loza, José. Instituto Alexander Fleming; Argentina
Fil: Coló, Federico. Instituto Médico Especializado Alexander Fleming; Argentina
Fil: Loza, Carlos Martín. Instituto Médico Especializado Alexander Fleming; Argentina
Fil: Fabiano, Verónica. Instituto Médico Especializado Alexander Fleming; Argentina
Fil: Maino, Merecedes. Instituto Médico Especializado Alexander Fleming; Argentina
Fil: Podhorzer, Ariel. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Fainboim, Leonardo. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Barrio, Maria Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina
Fil: Mordoh, Jose. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Levy, Estrella Mariel. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Materia
ADCC
CD85J
CETUXIMAB
EGFR
NK CELLS
TRIPLE NEGATIVE BREAST CANCER
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:11336/113604
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Overexpression of CD85j in TNBC patients inhibits Cetuximab-mediated NK-cell ADCC but can be restored with CD85j functional blockadeRoberti, María PaulaJuliá, Estefanía PaulaRocca, YamilaAmat, MoraBravo, Alicia InésLoza, JoséColó, FedericoLoza, Carlos MartínFabiano, VerónicaMaino, MerecedesPodhorzer, ArielFainboim, LeonardoBarrio, Maria MarcelaMordoh, JoseLevy, Estrella MarielADCCCD85JCETUXIMABEGFRNK CELLSTRIPLE NEGATIVE BREAST CANCERhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Clinical studies suggest that triple negative breast cancer (TNBC) patients with epidermal growth factor receptor (EGFR)-expressing tumors could benefit from therapy with Cetuximab, which targets EGFR. NK cells are the primary effectors of antibody (Ab)-dependent cell-mediated cytotoxicity (ADCC) and thus play a role in Ab-based therapies. We have previously described diminished levels of Cetuximab-mediated ADCC in vitro in patients with advanced breast cancer. Here, we investigated the potential causes of this NK-cell functional deficiency. We characterized NK-cell activating/inhibitory receptors in the peripheral blood of breast cancer patients and found CD85j inhibitory receptor overexpression. The capacity of NK cells to perform Cetuximab-triggered ADCC against TNBC cells correlated inversely with CD85j expression, even in the presence of the stimulatory cytokines IL-2 or IL-15. Hence, patients expressing high levels of CD85j had an impaired ability to lyse TNBC cells in the presence of Cetuximab. We also found that CD85j overexpression was associated with HLA-I and soluble HLA-G expression by tumors. A CD85j functional blockade with a CD85j antagonist Ab restored ADCC levels in breast cancer patients and reverted this negative effect. Our data suggest that strategies that overcome the hurdles of immune activation could improve Cetuximab clinical efficacy.Fil: Roberti, María Paula. Fundación Cáncer. Centro de Investigaciones Oncológicas; ArgentinaFil: Juliá, Estefanía Paula. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Rocca, Yamila. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Amat, Mora. Instituto Alexander Fleming; ArgentinaFil: Bravo, Alicia Inés. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Loza, José. Instituto Alexander Fleming; ArgentinaFil: Coló, Federico. Instituto Médico Especializado Alexander Fleming; ArgentinaFil: Loza, Carlos Martín. Instituto Médico Especializado Alexander Fleming; ArgentinaFil: Fabiano, Verónica. Instituto Médico Especializado Alexander Fleming; ArgentinaFil: Maino, Merecedes. Instituto Médico Especializado Alexander Fleming; ArgentinaFil: Podhorzer, Ariel. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fainboim, Leonardo. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Barrio, Maria Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Cáncer. Centro de Investigaciones Oncológicas; ArgentinaFil: Mordoh, Jose. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Levy, Estrella Mariel. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaWiley VCH Verlag2015-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/113604Roberti, María Paula; Juliá, Estefanía Paula; Rocca, Yamila; Amat, Mora; Bravo, Alicia Inés; et al.; Overexpression of CD85j in TNBC patients inhibits Cetuximab-mediated NK-cell ADCC but can be restored with CD85j functional blockade; Wiley VCH Verlag; European Journal of Immunology; 45; 5; 2-2015; 1560-15690014-2980CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1002/eji.201445353info:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/full/10.1002/eji.201445353info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:54:37Zoai:ri.conicet.gov.ar:11336/113604instacron: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 09:54:38.219CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Overexpression of CD85j in TNBC patients inhibits Cetuximab-mediated NK-cell ADCC but can be restored with CD85j functional blockade
title Overexpression of CD85j in TNBC patients inhibits Cetuximab-mediated NK-cell ADCC but can be restored with CD85j functional blockade
spellingShingle Overexpression of CD85j in TNBC patients inhibits Cetuximab-mediated NK-cell ADCC but can be restored with CD85j functional blockade
Roberti, María Paula
ADCC
CD85J
CETUXIMAB
EGFR
NK CELLS
TRIPLE NEGATIVE BREAST CANCER
title_short Overexpression of CD85j in TNBC patients inhibits Cetuximab-mediated NK-cell ADCC but can be restored with CD85j functional blockade
title_full Overexpression of CD85j in TNBC patients inhibits Cetuximab-mediated NK-cell ADCC but can be restored with CD85j functional blockade
title_fullStr Overexpression of CD85j in TNBC patients inhibits Cetuximab-mediated NK-cell ADCC but can be restored with CD85j functional blockade
title_full_unstemmed Overexpression of CD85j in TNBC patients inhibits Cetuximab-mediated NK-cell ADCC but can be restored with CD85j functional blockade
title_sort Overexpression of CD85j in TNBC patients inhibits Cetuximab-mediated NK-cell ADCC but can be restored with CD85j functional blockade
dc.creator.none.fl_str_mv Roberti, María Paula
Juliá, Estefanía Paula
Rocca, Yamila
Amat, Mora
Bravo, Alicia Inés
Loza, José
Coló, Federico
Loza, Carlos Martín
Fabiano, Verónica
Maino, Merecedes
Podhorzer, Ariel
Fainboim, Leonardo
Barrio, Maria Marcela
Mordoh, Jose
Levy, Estrella Mariel
author Roberti, María Paula
author_facet Roberti, María Paula
Juliá, Estefanía Paula
Rocca, Yamila
Amat, Mora
Bravo, Alicia Inés
Loza, José
Coló, Federico
Loza, Carlos Martín
Fabiano, Verónica
Maino, Merecedes
Podhorzer, Ariel
Fainboim, Leonardo
Barrio, Maria Marcela
Mordoh, Jose
Levy, Estrella Mariel
author_role author
author2 Juliá, Estefanía Paula
Rocca, Yamila
Amat, Mora
Bravo, Alicia Inés
Loza, José
Coló, Federico
Loza, Carlos Martín
Fabiano, Verónica
Maino, Merecedes
Podhorzer, Ariel
Fainboim, Leonardo
Barrio, Maria Marcela
Mordoh, Jose
Levy, Estrella Mariel
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ADCC
CD85J
CETUXIMAB
EGFR
NK CELLS
TRIPLE NEGATIVE BREAST CANCER
topic ADCC
CD85J
CETUXIMAB
EGFR
NK CELLS
TRIPLE NEGATIVE BREAST CANCER
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Clinical studies suggest that triple negative breast cancer (TNBC) patients with epidermal growth factor receptor (EGFR)-expressing tumors could benefit from therapy with Cetuximab, which targets EGFR. NK cells are the primary effectors of antibody (Ab)-dependent cell-mediated cytotoxicity (ADCC) and thus play a role in Ab-based therapies. We have previously described diminished levels of Cetuximab-mediated ADCC in vitro in patients with advanced breast cancer. Here, we investigated the potential causes of this NK-cell functional deficiency. We characterized NK-cell activating/inhibitory receptors in the peripheral blood of breast cancer patients and found CD85j inhibitory receptor overexpression. The capacity of NK cells to perform Cetuximab-triggered ADCC against TNBC cells correlated inversely with CD85j expression, even in the presence of the stimulatory cytokines IL-2 or IL-15. Hence, patients expressing high levels of CD85j had an impaired ability to lyse TNBC cells in the presence of Cetuximab. We also found that CD85j overexpression was associated with HLA-I and soluble HLA-G expression by tumors. A CD85j functional blockade with a CD85j antagonist Ab restored ADCC levels in breast cancer patients and reverted this negative effect. Our data suggest that strategies that overcome the hurdles of immune activation could improve Cetuximab clinical efficacy.
Fil: Roberti, María Paula. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina
Fil: Juliá, Estefanía Paula. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Rocca, Yamila. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Amat, Mora. Instituto Alexander Fleming; Argentina
Fil: Bravo, Alicia Inés. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; Argentina
Fil: Loza, José. Instituto Alexander Fleming; Argentina
Fil: Coló, Federico. Instituto Médico Especializado Alexander Fleming; Argentina
Fil: Loza, Carlos Martín. Instituto Médico Especializado Alexander Fleming; Argentina
Fil: Fabiano, Verónica. Instituto Médico Especializado Alexander Fleming; Argentina
Fil: Maino, Merecedes. Instituto Médico Especializado Alexander Fleming; Argentina
Fil: Podhorzer, Ariel. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Fainboim, Leonardo. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Barrio, Maria Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina
Fil: Mordoh, Jose. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Levy, Estrella Mariel. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
description Clinical studies suggest that triple negative breast cancer (TNBC) patients with epidermal growth factor receptor (EGFR)-expressing tumors could benefit from therapy with Cetuximab, which targets EGFR. NK cells are the primary effectors of antibody (Ab)-dependent cell-mediated cytotoxicity (ADCC) and thus play a role in Ab-based therapies. We have previously described diminished levels of Cetuximab-mediated ADCC in vitro in patients with advanced breast cancer. Here, we investigated the potential causes of this NK-cell functional deficiency. We characterized NK-cell activating/inhibitory receptors in the peripheral blood of breast cancer patients and found CD85j inhibitory receptor overexpression. The capacity of NK cells to perform Cetuximab-triggered ADCC against TNBC cells correlated inversely with CD85j expression, even in the presence of the stimulatory cytokines IL-2 or IL-15. Hence, patients expressing high levels of CD85j had an impaired ability to lyse TNBC cells in the presence of Cetuximab. We also found that CD85j overexpression was associated with HLA-I and soluble HLA-G expression by tumors. A CD85j functional blockade with a CD85j antagonist Ab restored ADCC levels in breast cancer patients and reverted this negative effect. Our data suggest that strategies that overcome the hurdles of immune activation could improve Cetuximab clinical efficacy.
publishDate 2015
dc.date.none.fl_str_mv 2015-02
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/11336/113604
Roberti, María Paula; Juliá, Estefanía Paula; Rocca, Yamila; Amat, Mora; Bravo, Alicia Inés; et al.; Overexpression of CD85j in TNBC patients inhibits Cetuximab-mediated NK-cell ADCC but can be restored with CD85j functional blockade; Wiley VCH Verlag; European Journal of Immunology; 45; 5; 2-2015; 1560-1569
0014-2980
CONICET Digital
CONICET
url http://hdl.handle.net/11336/113604
identifier_str_mv Roberti, María Paula; Juliá, Estefanía Paula; Rocca, Yamila; Amat, Mora; Bravo, Alicia Inés; et al.; Overexpression of CD85j in TNBC patients inhibits Cetuximab-mediated NK-cell ADCC but can be restored with CD85j functional blockade; Wiley VCH Verlag; European Journal of Immunology; 45; 5; 2-2015; 1560-1569
0014-2980
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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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/
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dc.publisher.none.fl_str_mv Wiley VCH Verlag
publisher.none.fl_str_mv Wiley VCH Verlag
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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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