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

• Published in: Oncogene Vol. 38; no. 15; pp. 2814 - 2829
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2019; Nature Publishing Group
• Subjects: 101/1; 13/31; 13/51; 38/109; 38/61; 631/250; 631/67/1347; 64/60; Adjuvant chemotherapy; Anthracyclines; Apoptosis; B cells; Breast cancer; Cancer cells; Cancer metastasis; Cancer patients; Cancer treatment; Care and treatment; CD4 antigen; CD8 antigen; Cell Biology; Chemotherapy; Complications and side effects; Development and progression; Dormancy; Doxorubicin; Epirubicin; Estrogen receptors; Estrogens; Human Genetics; Immune response; Immune system; Immunology; Interferon; Interferon regulatory factor 7; Internal Medicine; Lymphocytes T; Medicine; Medicine & Public Health; Metastases; Methotrexate; Novels; Oncology; Patients; Phenols (Class of compounds); Phenotypes; Retirement benefits; T cells; Tumor cells; Tumors; β-Interferon
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/s41388-018-0624-2

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.