Novel mechanisms of cytokine signaling on T-cell and MDSC function in glioma development

Malignant gliomas are the most common primary brain tumors with dismal prognosis. A growing line of evidence supports significant roles of immunosurveillance for prevention and regulation of cancer development. For example, tumor infiltrating T-cells are capable of killing tumor cells and are a positive prognostic factor for cancer patients. T-cell immune responses are classified into distinct effector cell types, type-1 or type-2, based on their cytokine-secreting profiles. We have demonstrated that tumor-specific type-1 T-cells, but not type-2 T-cells, can efficiently traffic into CNS tumor sites and mediate effective therapeutic efficacy via a type-1 chemokine CXCL10 and an integrin receptor VLA-4. Despite the importance of the type-1 T cell response, cancers, including GBMs, secrete numerous type-2 cytokines that promote tumor proliferation and immune escape. The hallmark cytokines of type-1 and type-2 immune responses are IFNs and IL-4, respectively. We therefore sought to better understand the role of IL-4 and IFN signaling in gliomas. We herein demonstrate that the miR-17-92 cluster is down-regulated in T-cells in both human and mouse tumors, dependent on IL-4R signaling. Further, ectopic expression of miR-17-92 cluster in T-cells resulted in enhanced IFN-γ and IL-2 production and resistance to activation induced cell death (AICD) (Aim 1). We next examined IL-4Rα on immunosuppressive myeloid derived suppressor cells (MDSCs). Interestingly we found that IL-4Rα was up-regulated on human and mouse glioma infiltrating, but not peripheral, MDSCs. Additionally, IL-4Rα expression promoted arginase activity, T-cell suppressing abilities and glioma growth (Aim 2). \ud As type I IFNs are important for anti-glioma type-1 immunity, we further examined how type I IFNs impact glioma patient prognosis. As there are multiple type I IFNs, our collaborators assisted us to identify potentially important genes by single nucleotide polymorphism (SNP) analysis. We found that IFN-pathway genes IFN- alpha receptor-1 (IFNAR1) and the IFN-alpha-8 (IFNA8) promoter both had SNPs associated with glioma prognosis. By luciferase assay and electrophoretic mobility shift assay (EMSA) we demonstrated that the A-allele, which is associated with better glioma patient survival, but not the C-allele of rs12553612 in the promoter region of IFNA8 allows for OCT-1 binding and activity of the IFNA8 promoter (Aim 3). \ud Overall, our data suggests that type-2 promoting has a dual role in suppressing glioma immunity through decreased T-cell functioning and enhanced MDSC function. Type-2 promoted suppression of glioma immunity can thus lead to better glioma patient prognosis, a significant public health achievement. \u