COX-2 inhibition improves immunotherapy and is associated with decreased numbers of myeloid-derived suppressor cells in mesothelioma. Celecoxib influences MDSC function

Abstract

BackgroundMyeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature cells that accumulates in tumour-bearing hosts. These cells are induced by tumour-derived factors (e.g. prostaglandins) and have a critical role in immune suppression. MDSC suppress T and NK cell function via increased expression of arginase I and production of reactive oxygen species (ROS) and nitric oxide (NO). Immune suppression by MDSC was found to be one of the main factors for immunotherapy insufficiency. Here we investigate if the in vivo immunoregulatory function of MDSC can be reversed by inhibiting prostaglandin synthesis by specific COX-2 inhibition focussing on ROS production by MDSC subtypes. In addition, we determined if dietary celecoxib treatment leads to refinement of immunotherapeutic strategies.MethodsMDSC numbers and function were analysed during tumour progression in a murine model for mesothelioma. Mice were inoculated with mesothelioma tumour cells and treated with cyclooxygenase-2 (COX-2) inhibitor celecoxib, either as single agent or in combination with dendritic cell-based immunotherapy.ResultsWe found that large numbers of infiltrating MDSC co-localise with COX-2 expression in those areas where tumour growth takes place. Celecoxib reduced prostaglandin E2 levels in vitro and in vivo. Treatment of tumour-bearing mice with dietary celecoxib prevented the local and systemic expansion of all MDSC subtypes. The function of MDSC was impaired as was noticed by reduced levels of ROS and NO and reversal of T cell tolerance; resulting in refinement of immunotherapy.ConclusionsWe conclude that celecoxib is a powerful tool to improve dendritic cell-based immunotherapy and is associated with a reduction in the numbers and suppressive function of MDSC. These data suggest that immunotherapy approaches benefit from simultaneously blocking cyclooxygenase-2 activity.

Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells

“…The reason for this particular potency of PGE 2 targeting may be explained by the ability of PGE 2 (and EP2 but not EP3/1 agonists) to exert a direct suppressive effect on CD8 ϩ T cells ( Figure 4F), apart from inducing the additional suppressive factors. These data highlight the mechanism of the previously reported involvement of PGE 2 in MDSC differentiation 17,[35][36][37]48 and help to reconcile previous observations that the induction of MDSCs and MDSC-related factors in different models can be mediated by the COX2 pathway 49 and EP4 36 or EP2 receptors,35 showing that these receptors have overlapping roles.The current observations contribute to our understanding of the mechanism of myeloid cell alterations in the complex system of tumor-associated immune dysfunction and the role of PGE 2 in this process. Because exposure to PGE 2 proportionally affects all cell populations in a tumor-inflammatory setting, the current data suggest that even though a short-term exposure to PGE 2 can induce the maturation of the already developed DCs, thus increasing their stimulatory function, 32,33 the continued presence of PGE 2 progressively affects the increasing proportion of differentiating DCs at early stages of their development, redirecting them toward MDSCs.…”

Tumor Microenvironment and Myeloid-Derived Suppressor Cells

“…In particular, the inhibition of COX-2 activity and PGE2 production reported to reduce the MDSC trafficking mediated by chemokines CXCR4/CXCL12 and CXCR1-CXCR2/CXCL8 [83] has been also shown to impair the MDSC-mediated immunosuppression through the down-regulation of ROS and NO production [117,118] or ARG-1 expression in these cells [119].…”

Cyclooxygenase-2, Epidermal Growth Factor Receptor, and Aromatase Signaling in Inflammation and Mesothelioma

“…Thus, reinforcing the evidence of COX-2 primary role in the pathogenesis and progression of malignant mesothelioma (36,37). Because of the lack of reliable treatment capable of achieving long-term control in patients with mesothelioma, these enzymes are becoming more and more credible as potential therapeutic targets (19,38,39). Celecoxib, a nonsteroidal anti-inflammatory drug (NSAID) and selective COX-2 inhibitor, in association with other drugs, is used in malignant mesothelioma clinical trials (Table 1).…”