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

Cancer Res. 2011 Apr 1;71(7):2664-74. doi: 10.1158/0008-5472.CAN-10-3055. Epub 2011 Feb 15.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Aspirin / pharmacology
  • CD8-Positive T-Lymphocytes / immunology
  • Celecoxib
  • Chemokine CCL2 / immunology
  • Chemokine CXCL10 / immunology
  • Cyclooxygenase 2 / biosynthesis
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 Inhibitors / pharmacology*
  • Dinoprostone / antagonists & inhibitors
  • Dinoprostone / biosynthesis
  • Female
  • Glioma / enzymology
  • Glioma / immunology
  • Glioma / pathology
  • Glioma / prevention & control*
  • Lysosomal-Associated Membrane Protein 1 / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Cells / drug effects*
  • Myeloid Cells / enzymology
  • Myeloid Cells / immunology
  • Myeloid Cells / pathology
  • Pyrazoles / pharmacology
  • Sulfonamides / pharmacology
  • T-Lymphocytes, Cytotoxic / immunology


  • Anti-Inflammatory Agents, Non-Steroidal
  • Chemokine CCL2
  • Chemokine CXCL10
  • Cyclooxygenase 2 Inhibitors
  • Lysosomal-Associated Membrane Protein 1
  • Pyrazoles
  • Sulfonamides
  • Cyclooxygenase 2
  • Celecoxib
  • Dinoprostone
  • Aspirin