COX-2 Blockade Suppresses Gliomagenesis by Inhibiting Myeloid-Derived Suppressor Cells
- 31 March 2011
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 71 (7), 2664-2674
- https://doi.org/10.1158/0008-5472.can-10-3055
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.Other Versions
This publication has 39 references indexed in Scilit:
- Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trialsThe Lancet, 2011
- Eicosanoids and cancerNature Reviews Cancer, 2010
- Advances in the genetics of glioblastoma: are we reaching critical mass?Nature Reviews Neurology, 2009
- Monocyte Chemoattractant Protein-1 (MCP-1): An OverviewJournal of Interferon & Cytokine Research, 2009
- Tumor-associated macrophages and the related myeloid-derived suppressor cells as a paradigm of the diversity of macrophage activationHuman Immunology, 2009
- Myeloid-derived suppressor cells as regulators of the immune systemNature Reviews Immunology, 2009
- Effective Immunotherapy against Murine Gliomas Using Type 1 Polarizing Dendritic Cells—Significant Roles of CXCL10Cancer Research, 2009
- De novo Induction of Genetically Engineered Brain Tumors in Mice Using Plasmid DNACancer Research, 2009
- Polymorphisms in the Interleukin-4 Receptor Gene are Associated with Better Survival in Patients with GlioblastomaClinical Cancer Research, 2008
- Ability of Mature Dendritic Cells to Interact with Regulatory T Cells Is Imprinted during MaturationCancer Research, 2008