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.
Highlights
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature cells that accumulates in tumour-bearing hosts
Since reactive oxygen species (ROS) is one of the principal factors leading to induction of T cell tolerance, we focused on the effects on ROS production by different MDSC populations during celecoxib-treatment
Identification of myeloid-derived suppressor cell subsets Splenocytes from mice that were inoculated with a lethal dose of AB1 tumour cells and placed on a control or celecoxib diet were stained for flowcytometric analysis
Summary
Myeloid-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 are a heterogeneous population of immature myeloid cells These cells can inhibit anti-tumour responses in an antigen-specific and in a non-specific way [1,2]. Antigen-specific suppression takes place in lymphoid organs and depends on reactive oxygen species (ROS) production, leading to T cell tolerance. Antigen-non-specific suppression takes place at the tumour the induction of T cell tolerance by MDSC subtypes need to be further explored. We investigated if ROS production by these different MDSC populations can be influenced
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