Avelumab, an IgG1 anti-PD-L1 immune checkpoint inhibitor, triggers NK cell-mediated cytotoxicity and cytokine production against Triple Negative Breast Cancer cells

Autores
Juliá, Estefanía Paula; Amante, Analía; Pampena, María Betina; Mordoh, Jose; Levy, Estrella Mariel
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The standard treatment for Triple Negative Breast Cancer (TNBC) patients is cytotoxic chemotherapy, but it is restricted since the duration of response is usually short. Blocking the PD-1/PD-L1 pathway through monoclonal antibodies (mAbs) appears to be a promising therapeutic strategy for TNBC patients. Avelumab is a human IgG1 anti-PD-L1 mAb being tested in clinical trials that may also trigger antibody-dependent cell-mediated cytotoxicity (ADCC) against cancer cells as an additional antitumor activity. In the present work, we studied in vitro Avelumab-mediated ADCC against a panel of TNBC cells with different PD-L1 expression using peripheral blood mononuclear cells (PBMC) or purified NK cells from healthy donors. We determined that Avelumab significantly enhanced NK-cell mediated cytotoxicity against TNBC cells and that tumor cells expressing higher levels of PD-L1 were more sensitive to Avelumab-mediated ADCC. IFN-? treatment upregulated PD-L1 expression in tumor cells but had a variable impact on Avelumab-mediated ADCC, which could be related to the simultaneous effect of IFN-? on the expression of NK cell ligands. Moreover, IL-2 and IL-15 stimulation of NK cells enhanced Avelumab-triggered cytokine production and degranulation along with increased lytic activity against tumor cells. Improving the treatment of TNBC remains still a considerable challenge. This in vitro study suggests that Avelumab-mediated ADCC, independently of the blockade of the PD-1/PD-L1 pathway, could be a valuable mechanism for tumor cell elimination in TNBC. Avelumab combination with immunomodulators such as IL-15 or IL-2 could be taken into consideration to increase the therapeutic efficacy of Avelumab in TNBC.
Fil: Juliá, Estefanía Paula. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Amante, Analía. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina
Fil: Pampena, María Betina. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Mordoh, Jose. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Levy, Estrella Mariel. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Materia
ADCC
AVELUMAB
IFN-?
IL-15
IL-2
PD-L1
TRIPLE NEGATIVE BREAST CANCER (TNBC)
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/176038
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/176038
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Avelumab, an IgG1 anti-PD-L1 immune checkpoint inhibitor, triggers NK cell-mediated cytotoxicity and cytokine production against Triple Negative Breast Cancer cellsJuliá, Estefanía PaulaAmante, AnalíaPampena, María BetinaMordoh, JoseLevy, Estrella MarielADCCAVELUMABIFN-?IL-15IL-2PD-L1TRIPLE NEGATIVE BREAST CANCER (TNBC)https://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3The standard treatment for Triple Negative Breast Cancer (TNBC) patients is cytotoxic chemotherapy, but it is restricted since the duration of response is usually short. Blocking the PD-1/PD-L1 pathway through monoclonal antibodies (mAbs) appears to be a promising therapeutic strategy for TNBC patients. Avelumab is a human IgG1 anti-PD-L1 mAb being tested in clinical trials that may also trigger antibody-dependent cell-mediated cytotoxicity (ADCC) against cancer cells as an additional antitumor activity. In the present work, we studied in vitro Avelumab-mediated ADCC against a panel of TNBC cells with different PD-L1 expression using peripheral blood mononuclear cells (PBMC) or purified NK cells from healthy donors. We determined that Avelumab significantly enhanced NK-cell mediated cytotoxicity against TNBC cells and that tumor cells expressing higher levels of PD-L1 were more sensitive to Avelumab-mediated ADCC. IFN-? treatment upregulated PD-L1 expression in tumor cells but had a variable impact on Avelumab-mediated ADCC, which could be related to the simultaneous effect of IFN-? on the expression of NK cell ligands. Moreover, IL-2 and IL-15 stimulation of NK cells enhanced Avelumab-triggered cytokine production and degranulation along with increased lytic activity against tumor cells. Improving the treatment of TNBC remains still a considerable challenge. This in vitro study suggests that Avelumab-mediated ADCC, independently of the blockade of the PD-1/PD-L1 pathway, could be a valuable mechanism for tumor cell elimination in TNBC. Avelumab combination with immunomodulators such as IL-15 or IL-2 could be taken into consideration to increase the therapeutic efficacy of Avelumab in TNBC.Fil: Juliá, Estefanía Paula. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Amante, Analía. Fundación Cáncer. Centro de Investigaciones Oncológicas; ArgentinaFil: Pampena, María Betina. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Mordoh, Jose. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Levy, Estrella Mariel. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFrontiers Media2018-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/176038Juliá, Estefanía Paula; Amante, Analía; Pampena, María Betina; Mordoh, Jose; Levy, Estrella Mariel; Avelumab, an IgG1 anti-PD-L1 immune checkpoint inhibitor, triggers NK cell-mediated cytotoxicity and cytokine production against Triple Negative Breast Cancer cells; Frontiers Media; Frontiers in Immunology; 9; 8-2018; 1-121664-3224CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/articles/10.3389/fimmu.2018.02140/fullinfo:eu-repo/semantics/altIdentifier/doi/10.3389/fimmu.2018.02140info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-11-26T09:11:27Zoai:ri.conicet.gov.ar:11336/176038instacron: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:34982025-11-26 09:11:27.968CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Avelumab, an IgG1 anti-PD-L1 immune checkpoint inhibitor, triggers NK cell-mediated cytotoxicity and cytokine production against Triple Negative Breast Cancer cells
title Avelumab, an IgG1 anti-PD-L1 immune checkpoint inhibitor, triggers NK cell-mediated cytotoxicity and cytokine production against Triple Negative Breast Cancer cells
spellingShingle Avelumab, an IgG1 anti-PD-L1 immune checkpoint inhibitor, triggers NK cell-mediated cytotoxicity and cytokine production against Triple Negative Breast Cancer cells
Juliá, Estefanía Paula
ADCC
AVELUMAB
IFN-?
IL-15
IL-2
PD-L1
TRIPLE NEGATIVE BREAST CANCER (TNBC)
title_short Avelumab, an IgG1 anti-PD-L1 immune checkpoint inhibitor, triggers NK cell-mediated cytotoxicity and cytokine production against Triple Negative Breast Cancer cells
title_full Avelumab, an IgG1 anti-PD-L1 immune checkpoint inhibitor, triggers NK cell-mediated cytotoxicity and cytokine production against Triple Negative Breast Cancer cells
title_fullStr Avelumab, an IgG1 anti-PD-L1 immune checkpoint inhibitor, triggers NK cell-mediated cytotoxicity and cytokine production against Triple Negative Breast Cancer cells
title_full_unstemmed Avelumab, an IgG1 anti-PD-L1 immune checkpoint inhibitor, triggers NK cell-mediated cytotoxicity and cytokine production against Triple Negative Breast Cancer cells
title_sort Avelumab, an IgG1 anti-PD-L1 immune checkpoint inhibitor, triggers NK cell-mediated cytotoxicity and cytokine production against Triple Negative Breast Cancer cells
dc.creator.none.fl_str_mv Juliá, Estefanía Paula
Amante, Analía
Pampena, María Betina
Mordoh, Jose
Levy, Estrella Mariel
author Juliá, Estefanía Paula
author_facet Juliá, Estefanía Paula
Amante, Analía
Pampena, María Betina
Mordoh, Jose
Levy, Estrella Mariel
author_role author
author2 Amante, Analía
Pampena, María Betina
Mordoh, Jose
Levy, Estrella Mariel
author2_role author
author
author
author
dc.subject.none.fl_str_mv ADCC
AVELUMAB
IFN-?
IL-15
IL-2
PD-L1
TRIPLE NEGATIVE BREAST CANCER (TNBC)
topic ADCC
AVELUMAB
IFN-?
IL-15
IL-2
PD-L1
TRIPLE NEGATIVE BREAST CANCER (TNBC)
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv The standard treatment for Triple Negative Breast Cancer (TNBC) patients is cytotoxic chemotherapy, but it is restricted since the duration of response is usually short. Blocking the PD-1/PD-L1 pathway through monoclonal antibodies (mAbs) appears to be a promising therapeutic strategy for TNBC patients. Avelumab is a human IgG1 anti-PD-L1 mAb being tested in clinical trials that may also trigger antibody-dependent cell-mediated cytotoxicity (ADCC) against cancer cells as an additional antitumor activity. In the present work, we studied in vitro Avelumab-mediated ADCC against a panel of TNBC cells with different PD-L1 expression using peripheral blood mononuclear cells (PBMC) or purified NK cells from healthy donors. We determined that Avelumab significantly enhanced NK-cell mediated cytotoxicity against TNBC cells and that tumor cells expressing higher levels of PD-L1 were more sensitive to Avelumab-mediated ADCC. IFN-? treatment upregulated PD-L1 expression in tumor cells but had a variable impact on Avelumab-mediated ADCC, which could be related to the simultaneous effect of IFN-? on the expression of NK cell ligands. Moreover, IL-2 and IL-15 stimulation of NK cells enhanced Avelumab-triggered cytokine production and degranulation along with increased lytic activity against tumor cells. Improving the treatment of TNBC remains still a considerable challenge. This in vitro study suggests that Avelumab-mediated ADCC, independently of the blockade of the PD-1/PD-L1 pathway, could be a valuable mechanism for tumor cell elimination in TNBC. Avelumab combination with immunomodulators such as IL-15 or IL-2 could be taken into consideration to increase the therapeutic efficacy of Avelumab in TNBC.
Fil: Juliá, Estefanía Paula. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Amante, Analía. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina
Fil: Pampena, María Betina. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Mordoh, Jose. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Levy, Estrella Mariel. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
description The standard treatment for Triple Negative Breast Cancer (TNBC) patients is cytotoxic chemotherapy, but it is restricted since the duration of response is usually short. Blocking the PD-1/PD-L1 pathway through monoclonal antibodies (mAbs) appears to be a promising therapeutic strategy for TNBC patients. Avelumab is a human IgG1 anti-PD-L1 mAb being tested in clinical trials that may also trigger antibody-dependent cell-mediated cytotoxicity (ADCC) against cancer cells as an additional antitumor activity. In the present work, we studied in vitro Avelumab-mediated ADCC against a panel of TNBC cells with different PD-L1 expression using peripheral blood mononuclear cells (PBMC) or purified NK cells from healthy donors. We determined that Avelumab significantly enhanced NK-cell mediated cytotoxicity against TNBC cells and that tumor cells expressing higher levels of PD-L1 were more sensitive to Avelumab-mediated ADCC. IFN-? treatment upregulated PD-L1 expression in tumor cells but had a variable impact on Avelumab-mediated ADCC, which could be related to the simultaneous effect of IFN-? on the expression of NK cell ligands. Moreover, IL-2 and IL-15 stimulation of NK cells enhanced Avelumab-triggered cytokine production and degranulation along with increased lytic activity against tumor cells. Improving the treatment of TNBC remains still a considerable challenge. This in vitro study suggests that Avelumab-mediated ADCC, independently of the blockade of the PD-1/PD-L1 pathway, could be a valuable mechanism for tumor cell elimination in TNBC. Avelumab combination with immunomodulators such as IL-15 or IL-2 could be taken into consideration to increase the therapeutic efficacy of Avelumab in TNBC.
publishDate 2018
dc.date.none.fl_str_mv 2018-08
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/11336/176038
Juliá, Estefanía Paula; Amante, Analía; Pampena, María Betina; Mordoh, Jose; Levy, Estrella Mariel; Avelumab, an IgG1 anti-PD-L1 immune checkpoint inhibitor, triggers NK cell-mediated cytotoxicity and cytokine production against Triple Negative Breast Cancer cells; Frontiers Media; Frontiers in Immunology; 9; 8-2018; 1-12
1664-3224
CONICET Digital
CONICET
url http://hdl.handle.net/11336/176038
identifier_str_mv Juliá, Estefanía Paula; Amante, Analía; Pampena, María Betina; Mordoh, Jose; Levy, Estrella Mariel; Avelumab, an IgG1 anti-PD-L1 immune checkpoint inhibitor, triggers NK cell-mediated cytotoxicity and cytokine production against Triple Negative Breast Cancer cells; Frontiers Media; Frontiers in Immunology; 9; 8-2018; 1-12
1664-3224
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.frontiersin.org/articles/10.3389/fimmu.2018.02140/full
info:eu-repo/semantics/altIdentifier/doi/10.3389/fimmu.2018.02140
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
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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