Abstract 1788: COX-2 blockade suppresses gliomagenesis by inhibiting CCL2-mediated accumulation of myeloid-derived suppressor cells

Abstract

Abstract Recent reports in epidemiology suggest yet unexplained roles of immunosurveillance in gliomagenesis and survival of glioma patients. For example, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) 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 induce immunoregulatory cells, such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells, in tumor-bearing hosts. In the current study, using a novel Sleeping Beauty transposon-mediated de novo mouse glioma model, we evaluated our hypothesis that COX-2 blockade by NSAIDs would suppress gliomagenesis by altering chemokine expression and immune cell attraction in glioma microenvironment, thereby promoting anti-glioma immunosurveillance. We chose acetylsalicylic acid (ASA; a non-selective COX-2 inhibitor) and celecoxib (a selective COX-2 inhibitor) as candidates of therapeutic agents. In wild type (WT) mice with developing gliomas, ASA-based treatment delayed glioma development only if the treatment was initiated simultaneously with glioma induction, but not after the tumor was established. In contrast, celecoxib-based treatment inhibited glioma development even if the treatment was initiated later. These data indicate that COX-2 plays an important role in gliomagenesis. Consistently, C57BL/6-background mice deficient for COX-2 gene (Cox2-deficient mice) demonstrated a significant delay in tumor growth when compared with the WT mice. Of importance, both the NSAID-treated and Cox2-deficient mice exhibited a decrease in systemic PGE2 levels when compared with the controls, which was concomitant with decreases in CCL2 and CD11b+Ly6CloLy6G+ MDSCs but increases in CXCL10 and CD8+CD107a+ CTLs in the glioma microenvironment. In addition, MDSC depletion by anti-Gr1 antibody treatment prolonged the survival of the WT mice developing gliomas, suggesting that COX2-induced MDSCs play an important role in gliomagenesis. We finally addressed the impacts of CCL2 and CXCL10 on the attraction of MDSCs and CTLs as well as gliomagenesis. With developing gliomas, Ccl2-deficient mice exhibited a decrease in MDSC accumulation in the glioma microenvironment, whereas Cxcl10-deficient mice exhibited a decrease in CTL accumulation. Taken together, these findings indicate important roles of the COX-2 pathway in gliomagenesis through CCL2-mediated MDSC accumulation and a reduction of CXCL10-mediated CTL infiltration into the glioma microenvironment, and suggest a possibility to develop NSAID-based prophylactic strategies for gliomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1788. doi:10.1158/1538-7445.AM2011-1788