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

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