COX-2 blockade suppresses gliomagenesis by inhibiting myeloid-derived suppressor cells

M Fujita, G Kohanbash, W Fellows-Mayle, RL Hamilton… - Cancer research, 2011 - AACR
M Fujita, G Kohanbash, W Fellows-Mayle, RL Hamilton, Y Komohara, SA Decker, JR Ohlfest…
Cancer research, 2011AACR
Epidemiologic studies have highlighted associations between the regular use of
nonsteroidal anti-inflammatory drugs (NSAID) and reduced glioma risks in humans. Most
NSAIDs function as COX-2 inhibitors that prevent production of prostaglandin E2 (PGE2).
Because PGE2 induces expansion of myeloid-derived suppressor cells (MDSC), we
hypothesized that COX-2 blockade would suppress gliomagenesis by inhibiting MDSC
development and accumulation in the tumor microenvironment (TME). In mouse models of …
Abstract
Epidemiologic studies have highlighted associations between the regular use of nonsteroidal anti-inflammatory drugs (NSAID) and reduced glioma risks in humans. Most NSAIDs function as COX-2 inhibitors that prevent production of prostaglandin E2 (PGE2). Because PGE2 induces expansion of myeloid-derived suppressor cells (MDSC), 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 PGE2 production and delayed glioma development. ASA treatment also reduced the MDSC-attracting chemokine CCL2 (C-C motif ligand 2) in the TME along with numbers of CD11b+Ly6GhiLy6Clo granulocytic MDSCs in both the bone marrow and the 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 (C-X-C motif chemokine 10) and infiltration of cytotoxic T lymphocytes (CTL) in the TME, consistent with a relief of MDSC-mediated immunosuppression. 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. Finally, Cxcl10-deficient mice exhibited reduced CTL infiltration of tumors, establishing that CXCL10 limited this pathway of immunosuppression. Taken together, our findings show that the COX-2 pathway promotes gliomagenesis by directly supporting systemic development of MDSCs and their accumulation in the TME, where they limit CTL infiltration. Cancer Res; 71(7); 2664–74. ©2011 AACR.
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