Abstract 1359: COX2 blockade suppresses glioma-genesis by promoting anti-glioma immunosurveillance
Authors: Fujita Mitsugu , Decker Stacy A. , Popescu Flavia , McDonald Heather A. , Kohanbash Gary , Ohlfest John R. , Okada Hideho 
Published: February 2011

Recent reports in epidemiology suggest yet unexplained roles of immunosurveillance in glioma-genesis and survival of glioma patients. For example, the use of nonsteroidal anti-inflammatory drugs (NSAID) has been shown to be associated with reduced occurrence of malignant glioma in humans. NSAIDs mediate their biological effects partially by suppression of cyclooxygenase (COX)-2 and its product prostaglandin (PG) E2, both of which are known to promote induction of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg). Using a novel Sleeping Beauty (SB) transposon-mediated de novo mouse glioma model, we evaluated our hypothesis that COX-2 blockade by NSAIDs would suppress glioma-genesis by promoting anti-glioma immunosurveillance. Because acetylsalicylic acid (ASA), in contrast to a selective COX-2 inhibitor celecoxib, did not demonstrate direct growth inhibition on cultured glioma cells at pharmacological concentrations, we utilized ASA to primarily address the impact of COX-2 blockade on immune cells. Neonatal C57BL/6 mice received SB-mediated glioma induction along with ASA (10 mg/kg) or control saline starting either at the time of glioma induction or after the establishment of solid glioma. Interestingly, ASA treatment starting at the time of SB-glioma induction rather than after the establishment of solid tumors reduced the rate and growth of glioma in the wild type (WT) mice. To elucidate the specific contributions of the COX-2 pathway, C57BL/6-background mice deficient for COX-2 gene (Cox2-deficient) received the SB-mediated glioma induction to be evaluated for tumor growth and changes in tumor microenvironment. The Cox2-deficient mice also demonstrated a significant delay in tumor growth when compared with the WT mice. Both the ASA-treated and Cox2-deficient mice demonstrated lower serum levels of PGE2, as well as marked reduction of Gr1+CD11b+ MDSCs and CD4+FoxP3+ Tregs in the glioma microenvironment when compared with the control mice. In addition, MDSC depletion by anti-Gr1 antibody treatment prolonged the survival of the WT mice developing gliomas, suggesting that these cells are at least partially responsible for glioma-genesis. We finally addressed the significance of endogeneous type-1 interferons (IFN) in the effects of COX-2 blockade because the type-1 IFNs are known to be central coordinators in anti-tumor immunosurveillance. To this end, C57BL/6-background mice deficient for type-1 IFN receptors (Ifnar1-deficient) received the SB-mediated glioma induction. In contrast to the WT mice, the Ifnar1-deficient mice did not delay tumor growth in response to ASA treatment. Taken together, these data suggest that COX-2 blockade by NSAIDs may reduce MDSCs and Tregs in the CNS microenvironment partially through the type-1 IFN pathways, thereby improving the immunosurveillance and prevention against gliomas.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1359.