Targeting myeloid derived suppressor cells to attenuate glioblastoma growth
Tyler Alban1*, Daniel Silver1, Balint Otvos1,3, Erin Mulkearns-Hubert1, James Hale1, Michael Vogelbaum2,3,4, Justin Lathia1,2,4
1Dept. of Cellular and Molecular Medicine; 2Dept. of Molecular Medicine; 3Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center; 4Case Western Comprehensive Cancer Center
Glioblastoma (GBM) is the most prevalent primary malignant brain tumor and has a median survival of only 12-15 months with standard-of-care therapies, which include surgery, radiation, and chemotherapy. Our laboratory previously identified myeloid-derived suppressor cells (MDSCs) as an immune cell population in GBM patient peripheral blood and the tumor microenvironment that correlates with decreased survival and a reduced immune response. In addition, macrophage migration inhibitory factor (MIF) was found to be a cancer stem cell (CSC) secreted cytokine that enhances MDSC function in GBM. When syngeneic glioma cells were depleted of MIF and intracranially injected into C57/Bl6 mice, a survival benefit was observed, which was not detected when repeated in immune-compromised mice. However, the molecular mechanism by which MIF acts on MDSCs remains unclear.Investigation of the MIF signaling axis in relation to MDSC biology is typically examined using samples from patients or from tumor-bearing mice, making it intrinsically difficult to study the molecular basis of their induction and activation. Therefore, we optimized an in vitro co-culture system that reproducibly generates GBM-induced MDSCs. The co-culture system is time dependent and relies on MIF secreting glioma cells to induce MDSCs.Additionally, MDSC induction can be diminished by MIF inhibitors. The MDSCs created were also functionally verified by use of a T cell activation assay which demonstrate that the co-culture induced MDSCs are able to inhibit T cell proliferation.This co-culture system is a platform for the mechanistic study of glioma-derived MDSCs, and will aide in determining MDSC targets for future immune therapies aimed at reducing the MDSC population to enhance the immune response.
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