Full Title COX-2 blockade suppresses gliomagenesis by inhibiting myeloid-derived suppressor cells Running Title COX-2 Blockade and Gliomagenesis Authors

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Epidemiological studies have highlighted associations between the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) and reduced glioma risks in humans. Most NSAIDs function as cyclooxygenase-2 (COX-2) inhibitors that prevent production of prostaglandin E 2 (PGE 2). Since PGE 2 induces expansion of myeloid-derived suppressor cells (MDSCs), we hypothesized that COX-2 blockade would suppress gliomagenesis by inhibiting MDSC development and accumulation in the tumor microenvironment (TME). In mouse models of glioma, treatment with the COX-2 inhibitors acetylsalicylic acid (ASA) or celecoxib inhibited systemic PGE 2 production and delayed glioma development. ASA treatment also reduced the MDSC-attracting chemokine CCL2 in the TME along with numbers of CD11b + Ly6G hi Ly6C lo granulocytic MDSCs in both the bone marrow and TME. In support of this evidence that COX-2 blockade blocked systemic development of MDSCs and their CCL2-mediated accumulation in the TME, there were defects in these processes in glioma-bearing Cox2-deficient and Ccl2-deficient mice. Conversely, these mice or ASA-treated wild-type mice displayed enhanced expression of CXCL10 and infiltration of cytotoxic T lymphocytes (CTL) in the TME, consistent with a relief of MDSC-mediated immune suppression. Antibody-mediated depletion of MDSCs delayed glioma growth in association with an increase in CXCL10 and CTLs in the TME, underscoring a critical role for MDSCs in glioma development. Lastly, Cxcl10-deficient mice exhibited reduced CTL infiltration of tumors, establishing that CXCL10 limited this pathway of immune suppression. Taken together, our findings show that the COX-2 pathway promotes gliomagenesis by directly supporting systemic development of MDSC and their accumulation in the TME, where they limit CTL infiltration. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Précis This study shows that the COX-2 pathway contributes to brain tumorigenesis via chemokine-mediated recruitment of an important class of immunosuppressive myeloid cells that drive immune escape in the tumor microenvironment, offering mechanistic support for the development of NSAID-based prophylactic strategies. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.