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 E 2 (PGE 2 ). Because PGE 2 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 PGE 2 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 þ Ly6Ghi 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. Cancer Res; 71(7); 2664-74. Ó2011 AACR.

Celecoxib promotes degranulation of CD8+ T cells in HPV-induced lesions of K14-HPV16 transgenic mice

“…These findings suggest that celecoxib reduces the number of tumour-infiltrating CTL while enhancing their effector functions. These data are in agreement with a previous study using glioma-bearing mice where COX2 -/-mice had increasing percentages of tumour-infiltrating CD8 + CD107a + lymphocytes [19]. This may be explained by another study reporting that COX-2 activity leads to CTL senescence and this trajectory may be opposed by COX-2 inhibition, as shown by increased levels of CD28 and interleukin-2 in CD8 + T cells [18].…”

“…This effect may explain how the abrogation of COX-2 signalling reduces tumour growth in mouse models of glioma [19] and mammary cancer [20]. In light of these findings, it is appealing to study whether CD8 + T cells present in HPV-induced lesions are affected by COX-2 inhibition.…”

TLR7-based cancer immunotherapy decreases intratumoral myeloid-derived suppressor cells and blocks their immunosuppressive function

“…12 As these cells are known to impair tumor immunity, different strategies have been applied to target MDSC in cancer. Several approaches are under investigation to inhibit these cells pharmacologically, including the induction of MDSC apoptosis (by gemcitabine, sunitinib, or 5-fluorouracil) [25][26][27] , the inhibition of MDSC function (with sildenafil and cyclooxygenase 2 inhibitors) 28,29 and the promotion of maturation of MDSC into nonsuppressive cells (all-trans retinoic acid, vitamin D). 30 Here, we have shown that TLR7 stimulation leads to the upregulation of maturation markers on MDSC in vitro, a finding that is in accordance with previous reports.…”

COX-2 promotes metastasis in nasopharyngeal carcinoma by mediating interactions between cancer cells and myeloid-derived suppressor cells

“…Recently, accumulating evidence has shown that a PGE2-COX-2-mediated positive feedback loop is essential for the induction of immunosuppressive factors secreted by human MDSCs 41 and that COX-2 is implicated in tumor angiogenesis, evasion of apoptosis, and induction of EMT. 42,43 Therefore, we suppressed the expression of COX-2 in TW03 and CNE1 cells using siRNAs targeting COX-2 (siCOX-2).…”