Decreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer models

Autores
Bottos, Alessia; Gotthardt, Dagmar; Gill, Jason W.; Gattelli, Albana; Frei, Anna; Tzankov, Alexandar; Sexl, Veronika; Wodnar Filipowicz, Aleksandra; Hynes, Nancy E.
Año de publicación
2016
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The JAK/STAT pathway is an attractive target for breast cancer therapy due to its frequent activation, and clinical trials evaluating JAK inhibitors (JAKi) in advanced breast cancer are ongoing. Using patient biopsies and preclinical models of breast cancer, we demonstrate that the JAK/STAT pathway is active in metastasis. Unexpectedly, blocking the pathway with JAKi enhances the metastatic burden in experimental and orthotopic models of breast cancer metastasis. We demonstrate that this prometastatic effect is due to the immunosuppressive activity of JAKi with ensuing impairment of NK-cell-mediated anti-tumour immunity. Furthermore, we show that immunostimulation with IL-15 overcomes the enhancing effect of JAKi on metastasis formation. Our findings highlight the importance of evaluating the effect of targeted therapy on the tumour environment. The impact of JAKi on NK cells and the potential value of immunostimulators to overcome the weakened tumour immunosurveillance, are worthwhile considering in the clinical setting of breast cancer.
Fil: Bottos, Alessia. Friedrich Miescher Institute for Biomedical Research; Suiza
Fil: Gotthardt, Dagmar. University of Veterinary Medicine; Austria
Fil: Gill, Jason W.. Friedrich Miescher Institute for Biomedical Research; Suiza
Fil: Gattelli, Albana. Friedrich Miescher Institute for Biomedical Research; Suiza. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Frei, Anna. Friedrich Miescher Institute for Biomedical Research; Suiza. Universidad de Basilea; Suiza
Fil: Tzankov, Alexandar. Universidad de Basilea; Suiza
Fil: Sexl, Veronika. University of Veterinary Medicine; Austria
Fil: Wodnar Filipowicz, Aleksandra. Universidad de Basilea; Suiza
Fil: Hynes, Nancy E.. Universidad de Basilea; Suiza. Friedrich Miescher Institute for Biomedical Research; Suiza
Materia
Breast cancer
Bone metastasis
Jak inhibitors
NK
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:11336/63073
Acceder
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repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Decreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer modelsBottos, AlessiaGotthardt, DagmarGill, Jason W.Gattelli, AlbanaFrei, AnnaTzankov, AlexandarSexl, VeronikaWodnar Filipowicz, AleksandraHynes, Nancy E.Breast cancerBone metastasisJak inhibitorsNKhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3The JAK/STAT pathway is an attractive target for breast cancer therapy due to its frequent activation, and clinical trials evaluating JAK inhibitors (JAKi) in advanced breast cancer are ongoing. Using patient biopsies and preclinical models of breast cancer, we demonstrate that the JAK/STAT pathway is active in metastasis. Unexpectedly, blocking the pathway with JAKi enhances the metastatic burden in experimental and orthotopic models of breast cancer metastasis. We demonstrate that this prometastatic effect is due to the immunosuppressive activity of JAKi with ensuing impairment of NK-cell-mediated anti-tumour immunity. Furthermore, we show that immunostimulation with IL-15 overcomes the enhancing effect of JAKi on metastasis formation. Our findings highlight the importance of evaluating the effect of targeted therapy on the tumour environment. The impact of JAKi on NK cells and the potential value of immunostimulators to overcome the weakened tumour immunosurveillance, are worthwhile considering in the clinical setting of breast cancer.Fil: Bottos, Alessia. Friedrich Miescher Institute for Biomedical Research; SuizaFil: Gotthardt, Dagmar. University of Veterinary Medicine; AustriaFil: Gill, Jason W.. Friedrich Miescher Institute for Biomedical Research; SuizaFil: Gattelli, Albana. Friedrich Miescher Institute for Biomedical Research; Suiza. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Frei, Anna. Friedrich Miescher Institute for Biomedical Research; Suiza. Universidad de Basilea; SuizaFil: Tzankov, Alexandar. Universidad de Basilea; SuizaFil: Sexl, Veronika. University of Veterinary Medicine; AustriaFil: Wodnar Filipowicz, Aleksandra. Universidad de Basilea; SuizaFil: Hynes, Nancy E.. Universidad de Basilea; Suiza. Friedrich Miescher Institute for Biomedical Research; SuizaNature Publishing Group2016-07info: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/11336/63073Bottos, Alessia; Gotthardt, Dagmar; Gill, Jason W.; Gattelli, Albana; Frei, Anna; et al.; Decreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer models; Nature Publishing Group; Nature Communications; 7; 7-2016; 1-122041-1723CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1038/ncomms12258info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/ncomms12258info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947169/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:24:21Zoai:ri.conicet.gov.ar:11336/63073instacron: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:34982025-09-29 10:24:21.929CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Decreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer models
title Decreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer models
spellingShingle Decreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer models
Bottos, Alessia
Breast cancer
Bone metastasis
Jak inhibitors
NK
title_short Decreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer models
title_full Decreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer models
title_fullStr Decreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer models
title_full_unstemmed Decreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer models
title_sort Decreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer models
dc.creator.none.fl_str_mv Bottos, Alessia
Gotthardt, Dagmar
Gill, Jason W.
Gattelli, Albana
Frei, Anna
Tzankov, Alexandar
Sexl, Veronika
Wodnar Filipowicz, Aleksandra
Hynes, Nancy E.
author Bottos, Alessia
author_facet Bottos, Alessia
Gotthardt, Dagmar
Gill, Jason W.
Gattelli, Albana
Frei, Anna
Tzankov, Alexandar
Sexl, Veronika
Wodnar Filipowicz, Aleksandra
Hynes, Nancy E.
author_role author
author2 Gotthardt, Dagmar
Gill, Jason W.
Gattelli, Albana
Frei, Anna
Tzankov, Alexandar
Sexl, Veronika
Wodnar Filipowicz, Aleksandra
Hynes, Nancy E.
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Breast cancer
Bone metastasis
Jak inhibitors
NK
topic Breast cancer
Bone metastasis
Jak inhibitors
NK
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 JAK/STAT pathway is an attractive target for breast cancer therapy due to its frequent activation, and clinical trials evaluating JAK inhibitors (JAKi) in advanced breast cancer are ongoing. Using patient biopsies and preclinical models of breast cancer, we demonstrate that the JAK/STAT pathway is active in metastasis. Unexpectedly, blocking the pathway with JAKi enhances the metastatic burden in experimental and orthotopic models of breast cancer metastasis. We demonstrate that this prometastatic effect is due to the immunosuppressive activity of JAKi with ensuing impairment of NK-cell-mediated anti-tumour immunity. Furthermore, we show that immunostimulation with IL-15 overcomes the enhancing effect of JAKi on metastasis formation. Our findings highlight the importance of evaluating the effect of targeted therapy on the tumour environment. The impact of JAKi on NK cells and the potential value of immunostimulators to overcome the weakened tumour immunosurveillance, are worthwhile considering in the clinical setting of breast cancer.
Fil: Bottos, Alessia. Friedrich Miescher Institute for Biomedical Research; Suiza
Fil: Gotthardt, Dagmar. University of Veterinary Medicine; Austria
Fil: Gill, Jason W.. Friedrich Miescher Institute for Biomedical Research; Suiza
Fil: Gattelli, Albana. Friedrich Miescher Institute for Biomedical Research; Suiza. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Frei, Anna. Friedrich Miescher Institute for Biomedical Research; Suiza. Universidad de Basilea; Suiza
Fil: Tzankov, Alexandar. Universidad de Basilea; Suiza
Fil: Sexl, Veronika. University of Veterinary Medicine; Austria
Fil: Wodnar Filipowicz, Aleksandra. Universidad de Basilea; Suiza
Fil: Hynes, Nancy E.. Universidad de Basilea; Suiza. Friedrich Miescher Institute for Biomedical Research; Suiza
description The JAK/STAT pathway is an attractive target for breast cancer therapy due to its frequent activation, and clinical trials evaluating JAK inhibitors (JAKi) in advanced breast cancer are ongoing. Using patient biopsies and preclinical models of breast cancer, we demonstrate that the JAK/STAT pathway is active in metastasis. Unexpectedly, blocking the pathway with JAKi enhances the metastatic burden in experimental and orthotopic models of breast cancer metastasis. We demonstrate that this prometastatic effect is due to the immunosuppressive activity of JAKi with ensuing impairment of NK-cell-mediated anti-tumour immunity. Furthermore, we show that immunostimulation with IL-15 overcomes the enhancing effect of JAKi on metastasis formation. Our findings highlight the importance of evaluating the effect of targeted therapy on the tumour environment. The impact of JAKi on NK cells and the potential value of immunostimulators to overcome the weakened tumour immunosurveillance, are worthwhile considering in the clinical setting of breast cancer.
publishDate 2016
dc.date.none.fl_str_mv 2016-07
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/11336/63073
Bottos, Alessia; Gotthardt, Dagmar; Gill, Jason W.; Gattelli, Albana; Frei, Anna; et al.; Decreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer models; Nature Publishing Group; Nature Communications; 7; 7-2016; 1-12
2041-1723
CONICET Digital
CONICET
url http://hdl.handle.net/11336/63073
identifier_str_mv Bottos, Alessia; Gotthardt, Dagmar; Gill, Jason W.; Gattelli, Albana; Frei, Anna; et al.; Decreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer models; Nature Publishing Group; Nature Communications; 7; 7-2016; 1-12
2041-1723
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1038/ncomms12258
info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/ncomms12258
info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947169/
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 Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
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 13.070432

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