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Peyvandi et al. J Cancer Metastasis Treat 2019;5:44  I  http://dx.doi.org/10.20517/2394-4722.2019.16                     Page 11 of 24

               Taken together, there is growing evidence to support the notion that chemotherapy, in particular those based
               on anthracyclines, can elicit an effective anti-tumor immune response in breast cancer, mainly in the TNBC
                        +
               and HER2  subtypes.

               CHEMOTHERAPY-INDUCED IMMUNOLOGICAL BREAST CANCER DORMANCY
               One important question emerging from these studies is whether the cytotoxic activity of chemotherapy
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               and the elicited immune response, dominated by CD8  T lymphocytes, may be sufficient to effectively kill
               cancer cells or whether additional mechanisms may be involved. This is particularly relevant to dormant
               DTC as these cells are naturally less responsive to chemotherapy due to the fact that they are not or low
               proliferative. We were interested in the possibility of whether a short chemotherapy treatment, induce a
               long-lasting immune response leading to immunological dormancy. We recently addressed this question
               experimentally [226] . To this end, we treated the TNBC-like 4T1 cells with high dose Methotrexate and
               Doxorubicin in vitro and characterized the in vitro and in vivo behavior of the surviving cells (MR20
               and DR500 derived from Methotrexate and Doxorubicin treatment, respectively). The hallmark of the
               surviving cell lines was the dormant phenotype at the primary (MR20 in the mammary gland) or at the
               metastatic (MR20 and DR500 in the lung) site. MR20 cells grew significantly slower in vitro compared to
               parental 4T1 cells and this was due to increased cell death, while there was no significant alteration in the
               cell cycle.  When injected orthotopically in the mammary fat pad of immunocompetent BALB/c mice,
               only about half of the MR20-injected mice developed tumors with a longer latency (between 6 week and
               4 months) compared to parental 4T1 cells (between 2 and 4 weeks). These tumor cells grew with nearly
               the same rate as parental 4T1 tumors and were highly metastatic. DR500 cells formed primary tumors but
               no lung metastases. Both conditions were consistent with dormancy. In BALB/c mice MR20 and DR500
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               cells twisted the immune response from CD11b  Gr1  MDSC-dominated to CD4/8 T cell, B cell and DC
               dominated response. When injected in vivo in immunodeficient NSG mice, however, treated cells formed
               tumors without latency. We then performed a genome wide gene expression analysis of parental 4T1, MR20
               and DR500 cells and the dominant trait observed was a type I IFN gene expression signature and the
               sustained activation of the IRF7/IFN-β/IFNAR pathway. Upregulated IRF7 expression in treated cancer cells
               was responsible for suppressed mobilization of CD11b  Gr1  MDSCs, increased expansion of DCs, T and B
                                                             +
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               lymphocytes and chemo resistance. Silencing IRF7 or blocking IFNAR1 resulted in escape from dormancy
               in vivo. Elevated levels of IFN-β were present in the blood of mice injected with dormant cells, while MR20
               cells escaping dormancy and forming late tumors no longer expressed IFN-β. Interestingly, the dormant
               D2.0R murine breast cancer cells that are generally considered as a model of cellular dormancy, also induced
               a T-cell twisted immune response and had a constitutive active IRF7/IFN-β/IFNAR pathway [Figure 3].
               To collect evidence that the activation of the type I IFN pathway was associated with a better response
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               to chemotherapy in patients, we monitored IFN-β levels in serum samples of ER  breast cancer patients
               treated with neoadjuvant chemotherapy (TOP trial NCT00162812). Patients with detectable IFN-β during
               neoadjuvant therapy had significantly longer distant metastasis free survival (DMFS) compared to patients
               with undetectable levels [226] .


               TYPE I IFN RESPONSE TO CHEMOTHERAPY MEDIATES IMMUNOLOGICAL DORMANCY IN

               BREAST CANCER
               Taken together our results demonstrate that sustained activation of the IFN-β/IFNAR/IRF7 signaling
               axis in chemotherapy-treated TNBC-like murine breast cancer cells instigates immunological dormancy.
               Elevated levels of IFN-β in the serum of TNBC patients during adjuvant therapy correlates with a shorter
               DMFS. Acute exposure of breast cancer cells to chemotherapy induced IFN-β expression [226] . Thus IFN-β
               may be considered as a potential therapeutic tool to improve chemotherapy efficacy and clinical outcome
               as well as a potential predictive biomarker to identify responding vs. non-responding patients. While the
               implication of type I IFN in dormancy is novel, previous reports have implicated it in acute anti-tumor
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