Abstract
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.
Highlights
Chemotherapy is widely used for the treatment of breast cancer
We demonstrate that sustained activation of the IFN-β/IFNAR/interferon regulatory factor 7 (IRF7) signaling axis in chemotherapy-treated ER− breast cancer cells instigates immunological dormancy
Upregulated IRF7 expression in treated cancer cells is responsible for reduced cell growth, suppressed mobilization of CD11b+Gr1+ MDSCs, increased expansion of dendritic cells (DC), T and B lymphocytes and chemoresistance
Summary
Chemotherapy is widely used for the treatment of breast cancer. While estrogen receptor negative (ER−) or triplenegative breast cancer (TNBC) is generally associated with unfavorable prognosis, neoadjuvant and adjuvant chemotherapies provide significant survival benefits to aboutBiotechnology, University of Helsinki, Helsinki, Finland one third of these patients [1]. ER− breast cancers relapse with a bimodal distribution, with peaks at 1–2 years and 4–5 years after surgery, followed by a tailed extension up to 10 years [2, 3] This profile suggests that disseminated tumor cells (DTC) evolve with a discontinuous growth kinetics [3, 4]. Three non-mutually exclusive forms of cancer dormancy have been described: cellular dormancy, whereby cancer cells enter a state of cell cycle arrest (i.e., G0-G1) and survive as disseminated single cells or small cell clusters; [9] angiogenic dormancy, a state where cancer cells proliferate but die of starvation due to lack angiogenesis; [10] immunological dormancy, in which disseminated cancer cells are kept under control by the immune system [9] in a process referred to as cancer immune-editing [11] This consists of three phases: elimination, when cancer cells are recognized and killed by the immune system; equilibrium, when the immune system controls but does not completely eliminate malignant cells, and escape, when residual tumor cells avoid immune control and resume growth [11, 12]. Mechanisms underline immunological dormancy in solid tumors, including breast cancer, are not well characterized
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