The Macrophage Migration Inhibitory Factor (MIF) is an inflammatory cytokine that has been well-characterized as a mediator of numerous inflammatory disease processes, including in the setting of breast cancer. Ongoing research has shown that increased levels of MIF in breast cancer patient serum and biopsy samples are a marker of poor prognosis. We have previously demonstrated that expression of MIF in the primary tumor is required for spontaneous pulmonary metastasis in the 4T1 murine model of breast cancer. We hypothesized that MIF, as a cytokine, would promote metastasis by controlling some aspect of the interaction between the tumor and the host immune system. This was supported by our observation that MIF expression was no longer required for metastasis in an immunodeficient host lacking T, B, and NK cells. Using flow cytometry, we discovered that MIF expression in the primary tumor increased the abundance of a subset of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. Furthermore, systemic depletion of MDSCs from tumor-bearing mice prevented spontaneous metastasis, suggesting that the MIF-induced increase in MDSCs is likely mediating the enhanced metastasis. These observations support a model in which MIF and MDSCs may be cooperating to protect the tumor cells from immune attack not only in the primary tumor, but also at sites of metastasis. Therefore, we hypothesize that MIF and MDSCs are functioning together to promote formation of a “metastatic niche” in the lung. Our ongoing studies aim to determine if MIF expression in the primary tumor drives matrix remodeling and/or establishment of an immunosuppressive microenvironment in the lungs of tumor-bearing mice, as well as whether inhibiting MIF pharmacologically can interrupt the process of niche formation. A more complete understanding of the role MIF plays in breast cancer development and metastasis will support deployment of MIF-targeted therapeutic interventions, as well as providing critical support for studies of how MIF inhibition might be combined with other immune-targeted therapies to enhance patient survival.
Citation Format: Kristen N. Balogh, Janet V. Cross. The macrophage migration inhibitory factor promotes breast cancer metastasis through interaction with the host immune response. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A152.
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