Type I interferon/IRF7 axis instigates chemotherapy-induced immunological dormancy in breast cancer.

Détails

Ressource 1Télécharger: Lan 2019.pdf (5412.01 [Ko])
Etat: Public
Version: de l'auteur
Licence: CC BY 4.0
ID Serval
serval:BIB_94A8CCA9EF90
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Type I interferon/IRF7 axis instigates chemotherapy-induced immunological dormancy in breast cancer.
Périodique
Oncogene
Auteur(s)
Lan Q., Peyvandi S., Duffey N., Huang Y.T., Barras D., Held W., Richard F., Delorenzi M., Sotiriou C., Desmedt C., Lorusso G., Rüegg C.
ISSN
1476-5594 (Electronic)
ISSN-L
0950-9232
Statut éditorial
Publié
Date de publication
04/2019
Peer-reviewed
Oui
Volume
38
Numéro
15
Pages
2814-2829
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
Neoadjuvant and adjuvant chemotherapies provide survival benefits to breast cancer patients, in particular in estrogen receptor negative (ER <sup>-</sup> ) cancers, by reducing rates of recurrences. It is assumed that the benefits of (neo)adjuvant chemotherapy are due to the killing of disseminated, residual cancer cells, however, there is no formal evidence for it. Here, we provide experimental evidence that ER <sup>-</sup> breast cancer cells that survived high-dose Doxorubicin and Methotrexate based chemotherapies elicit a state of immunological dormancy. Hallmark of this dormant phenotype is the sustained activation of the IRF7/IFN-β/IFNAR axis subsisting beyond chemotherapy treatment. Upregulation of IRF7 in treated cancer cells promoted resistance to chemotherapy, reduced cell growth and induced switching of the response from a myeloid derived suppressor cell-dominated immune response to a CD4 <sup>+</sup> /CD8 <sup>+</sup> T cell-dependent anti-tumor response. IRF7 silencing in tumor cells or systemic blocking of IFNAR reversed the state of dormancy, while spontaneous escape from dormancy was associated with loss of IFN-β production. Presence of IFN-β in the circulation of ER <sup>-</sup> breast cancer patients treated with neoadjuvant Epirubicin chemotherapy correlated with a significantly longer distant metastasis-free survival. These findings establish chemotherapy-induced immunological dormancy in ER <sup>-</sup> breast cancer as a novel concept for (neo)adjuvant chemotherapy activity, and implicate sustained activation of the IRF7/IFN-β/IFNAR pathway in this effect. Further, IFN-β emerges as a potential predictive biomarker and therapeutic molecule to improve outcome of ER <sup>-</sup> breast cancer patients treated with (neo)adjuvant chemotherapy.
Mots-clé
Animals, Antineoplastic Combined Chemotherapy Protocols/pharmacology, Biomarkers, Tumor/metabolism, Breast Neoplasms/drug therapy, Breast Neoplasms/metabolism, Cell Line, Tumor, Chemotherapy, Adjuvant/methods, Doxorubicin/pharmacology, Epirubicin/pharmacology, Female, Humans, Interferon Regulatory Factor-7/metabolism, Interferon Type I/metabolism, Interferon-beta/metabolism, Methotrexate/pharmacology, Mice, Mice, Inbred BALB C, Mice, Inbred NOD, Mice, Nude, Mice, SCID, Neoadjuvant Therapy/methods, Neoplasm Recurrence, Local/metabolism, Receptor, ErbB-2/metabolism
Pubmed
Web of science
Open Access
Oui
Création de la notice
12/01/2019 22:57
Dernière modification de la notice
18/07/2020 6:09
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