Article

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

Department of Pulmonary Medicine, Erasmus MC Rotterdam, The Netherlands.
BMC Cancer (Impact Factor: 3.32). 08/2010; 10:464. DOI: 10.1186/1471-2407-10-464
Source: PubMed

ABSTRACT 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 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.
MDSC 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.
We 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.
We 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.

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    • "The effect of COX-2 inhibition on MDSC function is not surprising as this has been established with other tumor types (45). Our observations indicate that KCM cells express higher levels of COX-2 and secrete higher levels of PGE2 than KCKO cells (Figures 5A,D–F). "
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    • "As described above, intratumoral ARG activity can be sustained by other factors, such as COX, acting on tumor-infiltrating myeloid cells. In several preclinical trials the use of COX2 inhibitors, such as celecoxib, down-regulated ARG1 expression, delayed tumor growth, and stimulated anti-tumor response (81, 170–172). In a mouse model of mesothelioma, Celecoxib improved survival when used in combination with DC-based immunotherapy (172). "
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