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

Our plain-English summary of COX-2 inhibition improves immunotherapy and is associated with decreased numbers of myeloid-derived suppressor cells in mesothelioma. Celecoxib influences MDSC function, by J.D. Veltman, M.E. Lambers, M. van Nimwegen, et al (BMC Cancer, 2010).

The study

• Authors: J.D. Veltman, M.E. Lambers, M. van Nimwegen, R.W. Hendriks, H.C. Hoogsteden, J.G. Aerts, J.P. Hegmans
• Journal: BMC Cancer
• Published: 2010;10:464
• Cited by: 241 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

In plain English

This was a laboratory experiment in mice. It did not study asbestos exposure or people. Female BALB/c mice were injected with AB1 mouse mesothelioma cells and fed a diet containing celecoxib, a selective COX-2 inhibitor, either alone or with dendritic cell-based immunotherapy. The authors tracked myeloid-derived suppressor cells (MDSC), immune cells that can suppress anti-tumour responses. Mice on celecoxib had significantly fewer MDSC in the spleen at day 10 and day 22 (p = 0.034 and p = 0.031). They also had significantly lower ROS production by two MDSC subtypes and lower PGE2 levels in peritoneal washings (p = 0.0061). Spleen cells from control-diet mice reduced the tumour-killing capacity of cells from immunotherapy-treated mice; spleen cells from celecoxib-fed mice did not. In groups of 6 mice, combined treatment improved survival compared with no treatment (p = 0.027). Celecoxib alone or immunotherapy alone did not significantly improve survival. The authors concluded that celecoxib reduced MDSC numbers and suppressive function, which was associated with a beneficial effect of immunotherapy. They stated that they could not verify a direct causal link.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment (mouse model of mesothelioma), with laboratory cell-culture and immune-function assays
• Who was studied: Female BALB/c mice, 6 to 8 weeks old, housed at the animal facility of Erasmus MC, Rotterdam, the Netherlands. The survival experiment used 4 groups of 6 mice. Other experiments used smaller numbers per group (for example n = 5/5 at day 10, n = 7 untreated versus n = 8 celecoxib-treated for tumour sections and PGE2).
• Exposure: No asbestos exposure was studied. On day 0, mice were injected with a lethal dose of 0.5 million AB1 mouse mesothelioma cells. They were then given a control diet or a celecoxib diet (500 mg celecoxib/kg). Some mice also received dendritic cell-based immunotherapy: 1 million tumour-lysate-loaded dendritic cells, given at day 10 as a deliberately suboptimal protocol.
• Main results:
  • Total MDSC numbers in the spleen were significantly lower in celecoxib-fed tumour-bearing mice than in control-diet mice at day 10 and at day 22 (p = 0.034 and p = 0.031).
  • At day 10 (n = 5 per group), celecoxib-fed mice had a significant reduction in the PMN-MDSC subtype (p = 0.021).
  • ROS production (mean fluorescent intensity) was significantly lower in MO-MDSC (p = 0.015) and in Gr-1low subset 2 MDSC (p = 0.017) from celecoxib-fed mice. ROS production by macrophages did not change significantly (p = 0.14).
  • PGE2 levels in peritoneal washings were lower in celecoxib-treated mice (n = 8) than in untreated mice (n = 7), p = 0.0061. No COX-2 expression was found in tumour sections from celecoxib-fed mice.
  • Spleen cells from control-diet tumour-bearing mice significantly reduced the tumour-cell killing by spleen cells from immunotherapy-treated mice (p = 0.0002). Spleen cells from celecoxib-fed mice did not (p = 0.887).
  • In the survival experiment (6 mice per group, each compared with no treatment), celecoxib combined with immunotherapy improved survival (p = 0.027). Celecoxib alone (p = 0.305) and immunotherapy alone (p = 0.456 in the figure legend) did not.
• The authors' conclusion: The authors concluded that celecoxib reduces the numbers and suppressive function of MDSC, and that this was associated with a beneficial effect of dendritic cell-based immunotherapy in this mouse model.
• Limitations the authors state:
  • The authors could not verify that the improved anti-tumour response was directly caused by the reduction in MDSC.
  • Because COX-2 and PGE2 take part in many cellular processes, the authors stated it is difficult to isolate the effect of a COX-2 inhibitor on MDSC in living animals.
  • The different MDSC subtypes could not be distinguished in tumour tissue with the available markers.
  • MDSC numbers or function may differ in other tumour cell lines or tumour models.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Immunotherapy, Mesothelioma, Reactive Oxygen Species (ROS).

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