PMID- 20804550
OWN - NLM
STAT- MEDLINE
DCOM- 20110203
LR  - 20211020
IS  - 1471-2407 (Electronic)
IS  - 1471-2407 (Linking)
VI  - 10
DP  - 2010 Aug 30
TI  - COX-2 inhibition improves immunotherapy and is associated with decreased numbers 
      of myeloid-derived suppressor cells in mesothelioma. Celecoxib influences MDSC 
      function.
PG  - 464
LID - 10.1186/1471-2407-10-464 [doi]
AB  - 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.
FAU - Veltman, Joris D
AU  - Veltman JD
AD  - Department of Pulmonary Medicine, Erasmus MC Rotterdam, The Netherlands.
FAU - Lambers, Margaretha E H
AU  - Lambers ME
FAU - van Nimwegen, Menno
AU  - van Nimwegen M
FAU - Hendriks, Rudi W
AU  - Hendriks RW
FAU - Hoogsteden, Henk C
AU  - Hoogsteden HC
FAU - Aerts, Joachim G J V
AU  - Aerts JG
FAU - Hegmans, Joost P J J
AU  - Hegmans JP
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100830
PL  - England
TA  - BMC Cancer
JT  - BMC cancer
JID - 100967800
RN  - 0 (Cyclooxygenase 2 Inhibitors)
RN  - 0 (Pyrazoles)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Sulfonamides)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - EC 1.14.99.1 (Cyclooxygenase 2)
RN  - JCX84Q7J1L (Celecoxib)
RN  - K7Q1JQR04M (Dinoprostone)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Celecoxib
MH  - Cyclooxygenase 2/chemistry/*metabolism
MH  - Cyclooxygenase 2 Inhibitors/*pharmacology
MH  - Dendritic Cells/immunology/metabolism/pathology
MH  - Dinoprostone/metabolism
MH  - Disease Models, Animal
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Female
MH  - Flow Cytometry
MH  - Immune Tolerance
MH  - Immunoenzyme Techniques
MH  - *Immunotherapy
MH  - Mesothelioma/enzymology/*immunology/*therapy
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Myeloid Cells/*immunology/pathology/transplantation
MH  - Nitric Oxide/metabolism
MH  - Pyrazoles/*pharmacology
MH  - Reactive Oxygen Species/metabolism
MH  - Sulfonamides/*pharmacology
MH  - T-Lymphocytes/immunology/metabolism/pathology
PMC - PMC2939552
EDAT- 2010/09/02 06:00
MHDA- 2011/02/04 06:00
PMCR- 2010/08/30
CRDT- 2010/09/01 06:00
PHST- 2010/03/24 00:00 [received]
PHST- 2010/08/30 00:00 [accepted]
PHST- 2010/09/01 06:00 [entrez]
PHST- 2010/09/02 06:00 [pubmed]
PHST- 2011/02/04 06:00 [medline]
PHST- 2010/08/30 00:00 [pmc-release]
AID - 1471-2407-10-464 [pii]
AID - 10.1186/1471-2407-10-464 [doi]
PST - epublish
SO  - BMC Cancer. 2010 Aug 30;10:464. doi: 10.1186/1471-2407-10-464.