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

Lan, Qiang; Peyvandi, Sanam; Duffey, Nathalie; Huang, Yu-Ting; Barras, David; Held, Werner; Richard, François; Delorenzi, Mauro; Sotiriou, Christos; Desmedt, Christine; Lorusso, Girieca; Rüegg, Curzio

doi:10.1038/s41388-018-0624-2

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Journal article

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

Lan, Qiang Pathology Unit, Department of Oncology, Microbiology and, Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Switzerland - National Center for Competence in Research (NCCR), Molecular Oncology, Swiss Institute for Experimental Cancer Research, (ISREC)-Ecole Polytechnique Fédérale de Lausanne, Switzerland - Developmental Biology Program, Institute of Biotechnology, University of Helsinki, Finland
Peyvandi, Sanam Pathology Unit, Department of Oncology, Microbiology and, Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Switzerland
Duffey, Nathalie Pathology Unit, Department of Oncology, Microbiology and, Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Switzerland
Huang, Yu-Ting Pathology Unit, Department of Oncology, Microbiology and, Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Switzerland - National Center for Competence in Research (NCCR), Molecular Oncology, Swiss Institute for Experimental Cancer Research, (ISREC)-Ecole Polytechnique Fédérale de Lausanne, Switzerland
Barras, David SIB-Swiss Institute of Bioinformatics, Lausanne, Switzerland
Held, Werner Ludwig Institute for Cancer Research, Epalinges, Switzerland - Department of Fundamental Oncology, University of Lausanne, Switzerland
Richard, François Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Belgium
Delorenzi, Mauro SIB-Swiss Institute of Bioinformatics, Lausanne, Switzerland - Ludwig Institute for Cancer Research, Epalinges, Switzerland - Department of Fundamental Oncology, University of Lausanne, Switzerland
Sotiriou, Christos Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Belgium
Desmedt, Christine Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Belgium
Lorusso, Girieca Pathology Unit, Department of Oncology, Microbiology and, Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Switzerland - National Center for Competence in Research (NCCR), Molecular Oncology, Swiss Institute for Experimental Cancer Research, (ISREC)-Ecole Polytechnique Fédérale de Lausanne, Switzerland
Rüegg, Curzio Pathology Unit, Department of Oncology, Microbiology and, Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Switzerland - National Center for Competence in Research (NCCR), Molecular Oncology, Swiss Institute for Experimental Cancer Research, (ISREC)-Ecole Polytechnique Fédérale de Lausanne, Switzerland - Swiss Integrative Center for Human Health, Fribourg, Switzerland

2019

Published in:

Oncogene. - 2019, vol. 38, no. 15, p. 2814–2829

English Neoadjuvant and adjuvant chemotherapies provide survival benefits to breast cancer patients, in particular in estrogen receptor negative (ER−) 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− 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+/CD8+ 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− 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− 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− breast cancer patients treated with (neo)adjuvant chemotherapy.

Faculty

Faculté des sciences et de médecine

Department

Médecine 3ème année

Language