title: COX-2 blockade suppresses gliomagenesis by inhibiting myeloid-derived suppressor cells.
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(+)Ly6G(hi)Ly6C(lo) 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.
authors.affiliation: Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Fujita
authors.forename: Gary
authors.initials: G
authors.lastname: Kohanbash
authors.forename: Wendy
authors.initials: W
authors.lastname: Fellows-Mayle
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Hamilton
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Komohara
authors.forename: Stacy A
authors.initials: SA
authors.lastname: Decker
authors.forename: John R
authors.initials: JR
authors.lastname: Ohlfest
authors.forename: Hideho
authors.initials: H
authors.lastname: Okada
mesh_terms: D000483:Alleles; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D000068579:Celecoxib; D018932:Chemokine CCL2 / Q000276:immunology; D054357:Chemokine CXCL10 / Q000276:immunology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D005260:Female; D005910:Glioma / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D052118:Lysosomal-Associated Membrane Protein 1 / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; D052246:Cyclooxygenase 2 Inhibitors; D052118:Lysosomal-Associated Membrane Protein 1; D011720:Pyrazoles; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D015232:Dinoprostone; D001241:Aspirin