THE ROLE OF MYELOID DERIVED SUPPRESSOR CELLS (MDSCS) IN TUMOR-INDUCED IMMUNOSUPPRESSION IN HUMAN AND MURINE GLIOMAS

BACKGROUND: (blind field) METHODS: To further study the biology of MDSCs in GBM, we have evaluated two preclinical models of GBM (RCAS tVA, GL261 orthografts) and observed a similar magnitude of glioma-induced elevation of circulating MDSCs as we observed in GBM patients. RESULTS: With use of immunofluorescent, antibody-based cellular labeling techniques, we have identified MDSCs within primary human and murine glioma tumor samples, and started to identify the niche to which MDSCs hone within these tumors. Further, we have observed an immunosuppressive phenotype marked by staining of MDSCs for arginase I, a known mediator capable of reducing cytotoxic T cell suppressor function. We also have observed co-localization between MDSCs and cancer stem cells (CSCs) in both human tissues and mouse models, leading to the hypothesis that CSCs recruit MDSCs to the tumor microenvironment, promote their survival, and that MDSCs are at least in part responsible for the immune-evasive properties of CSCs. Growth of gliomas in mice has been associated with expansion of the arginase-producing subset of MDSCs within bone marrow, and increased levels of arginase-secreting MDSCs within the glioma microenvironment. In vitro studies with isolated murine MDSCs have demonstrated that CSC conditioned media promotes decreased apoptosis and increased arginase production by these cells. Finally, treatment of glioma-bearing mice with sunitinib, a signal transduction inhibitor that has established anti-MDSC properties, resulted in a reduction in circulating and tumor-infiltrating MDSCs, increased T cell infiltration, and prolonged survival. CONCLUSIONS: Taken together, these results suggest a critical role by which gliomas are able to promote immunosuppression through the recruitment of MDSCs via CSCs into tumors and subsequent interaction of recruited MDSCs with tumor-infiltrating T cells. SECONDARY CATEGORY: n/a.