Gliomas are the most common primary brain tumor and one of the most lethal solid tumors. Mechanistic studies into identification of novel biomarkers are needed to develop new therapeutic strategies for this deadly disease. The objective for this study was to explore the potential direct impact of IL-17−IL-17R interaction in gliomas. Immunohistochemistry and flow cytometry analysis of 12 tumor samples obtained from patients with high grade gliomas revealed that a considerable population (2–19%) of cells in all malignant gliomas expressed IL-17RA, with remarkable co-expression of the glioma stem cell (GSC) markers CD133, Nestin, and Sox2. IL-17 enhanced the self-renewal of GSCs as determined by proliferation and Matrigel® colony assays. IL-17 also induced cytokine/chemokine (IL-6, IL-8, interferon-γ-inducible protein [IP-10], and monocyte chemoattractant protein-1 [MCP-1]) secretion in GSCs, which were differentially blocked by antibodies against IL-17R and IL-6R. Western blot analysis showed that IL-17 modulated the activity of signal transducer and activator of transcription 3 (STAT3), nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), glycogen synthase kinase-3β (GSK-3β) and β-catenin in GSCs. While IL-17R-mediated secretion of IL-6 and IL-8 were significantly blocked by inhibitors of NF-κB and STAT3; NF-κB inhibitor was more potent than STAT3 inhibitor in blocking IL-17-induced MCP-1 secretion. Overall, our results suggest that IL-17–IL-17R interaction in GSCs induces an autocrine/paracrine cytokine feedback loop, which may provide an important signaling component for maintenance/self-renewal of GSCs via constitutive activation of both NF-κB and STAT3. The results also strongly implicate IL-17R as an important functional biomarker for therapeutic targeting of GSCs.

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Malignant gliomas are the most common primary brain tumors with approximately 22,000 cases per year. In spite of aggressive surgery, radiotherapy and chemotherapeutic regimens, the median survival of patients with malignant gliomas is a dismal 15 months. The objective of our study was to explore the adjuvant therapeutic potential and associated molecular mechanisms of natural polyphenols stilbenes in malignant gliomas. Recent studies have demonstrated the efficacy of stilbenes in extracranial tumor models. Stilbenes, including resveratrol, were bioavailable in the brain even after low dose oral administration and there was no toxicity to normal tissue. On the contrary, these compounds were found to be neuroprotective in Alzheimer's disease models. Mechanistically, stilbenes modulate NF-κB, STAT3, wnt/β-catenin signaling and also inhibits antiapoptotic protein Bcl-xl. While these molecules are critical in imparting chemoresistance, they are also pivotal in inducing immune-resistance and pro-tumor immune infiltration in gliomas. We hypothesized that stilbenes enhance the efficacy of chemotherapy while also inhibiting immune-suppression and -resistance in malignant gliomas via overlapping molecular mechanisms. We observed significant positive interaction between Temozolomide and Resveratrol for inhibition of glioma proliferation. Resveratrol induced apoptosis in gliomas via inhibition of Bcl-2 and Bcl-xl, while STAT3 activity was also inhibited. Importantly, Resveratrol significantly enhanced the expression of TRAIL-R2 and MIC A/B in gliomas, making them vulnerable to lysis by CTLs and NK cells. Studies are underway to determine combined effect of DC-based immunotherapy and stilbenes against malignant gliomas using syngeneic, orthotopic mouse glioma models. The results can have significant impact in developing novel adjuvant studies to improve survival in patients with malignant gliomas. Citation Format: Chandramouli Mandalaparty, Andrew Huang, Sandeep Mittal, Agnes M. Rimando, Q. Ping Dou, Prahlad Parajuli. Immuno-sensitization of malignant gliomas by natural polyphenols. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3982. doi:10.1158/1538-7445.AM2013-3982