Intratumoral COX-2 inhibition enhances GM-CSF immunotherapy against established mouse GL261 brain tumors.
Eberstål, Sofia LU ; Sandén, Emma LU ; Fritzell, Sara LU ; Darabi, Anna LU ; Visse, Edward LU and Siesjö, Peter LU
(2014)
In International Journal of Cancer
134(11).
p.2748-2753
- Abstract
- Immunotherapy has shown effectiveness against experimental malignant brain tumors, but the clinical results have been less convincing most likely due to immunosuppression. Prostaglandin E2 (PGE2 ) is the key immunosuppressive product of cyclooxygenase-2 (COX-2) and increased levels of PGE2 and COX-2 have been shown in several tumor types including brain tumors. In the current study, we report enhanced cure rate of mice with established mouse GL261 brain tumors when immunized with granulocyte macrophage-colony stimulating factor (GM-CSF) secreting tumor cells and simultaneously treated with the selective COX-2 inhibitors parecoxib systemically (5 mg/kg/day; 69% cure rate) or valdecoxib intratumorally (5.3 µg/kg/day; 63% cure rate). Both... (More)
- Immunotherapy has shown effectiveness against experimental malignant brain tumors, but the clinical results have been less convincing most likely due to immunosuppression. Prostaglandin E2 (PGE2 ) is the key immunosuppressive product of cyclooxygenase-2 (COX-2) and increased levels of PGE2 and COX-2 have been shown in several tumor types including brain tumors. In the current study, we report enhanced cure rate of mice with established mouse GL261 brain tumors when immunized with granulocyte macrophage-colony stimulating factor (GM-CSF) secreting tumor cells and simultaneously treated with the selective COX-2 inhibitors parecoxib systemically (5 mg/kg/day; 69% cure rate) or valdecoxib intratumorally (5.3 µg/kg/day; 63% cure rate). Both combined therapies induced a systemic anti-tumor response of proliferating CD4(+) and CD8(+) T cells and further analysis revealed T helper 1 (Th 1) cell supremacy. The GL261 tumor cell line produced very low levels of PGE2 in vitro and co-staining at the tumor site demonstrated that a large fraction of the COX-2(+) cells were derived from CD45(+) immune cells and more specifically macrophages (F4/80(+) ), indicating that tumor-infiltrating immune cells constitute the primary source of COX-2 and PGE2 in this model. We conclude that intratumoral COX-2 inhibition potentiates GM-CSF immunotherapy against established brain tumors at substantially lower doses than systemic administration. These findings underscore the central role of targeting COX-2 during immunotherapy and implicate intratumoral COX-2 as the primary target. © 2013 Wiley Periodicals, Inc. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/4179249
- author
- Eberstål, Sofia
LU
; Sandén, Emma
LU
; Fritzell, Sara
LU
; Darabi, Anna
LU
; Visse, Edward
LU
and Siesjö, Peter
LU
- organization
- publishing date
- 2014
- type
- Contribution to journal
- publication status
- published
- subject
- in
- International Journal of Cancer
- volume
- 134
- issue
- 11
- pages
- 2748 - 2753
- publisher
- John Wiley & Sons Inc.
- external identifiers
-
- pmid:24243648
- wos:000332801700025
- scopus:84896390675
- pmid:24243648
- ISSN
- 0020-7136
- DOI
- 10.1002/ijc.28607
- language
- English
- LU publication?
- yes
- id
- c8a5c7c3-93f7-401e-ab37-245ee97083e9 (old id 4179249)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/24243648?dopt=Abstract
- date added to LUP
- 2016-04-01 09:50:02
- date last changed
- 2022-01-25 17:07:26
@article{c8a5c7c3-93f7-401e-ab37-245ee97083e9,
abstract = {{Immunotherapy has shown effectiveness against experimental malignant brain tumors, but the clinical results have been less convincing most likely due to immunosuppression. Prostaglandin E2 (PGE2 ) is the key immunosuppressive product of cyclooxygenase-2 (COX-2) and increased levels of PGE2 and COX-2 have been shown in several tumor types including brain tumors. In the current study, we report enhanced cure rate of mice with established mouse GL261 brain tumors when immunized with granulocyte macrophage-colony stimulating factor (GM-CSF) secreting tumor cells and simultaneously treated with the selective COX-2 inhibitors parecoxib systemically (5 mg/kg/day; 69% cure rate) or valdecoxib intratumorally (5.3 µg/kg/day; 63% cure rate). Both combined therapies induced a systemic anti-tumor response of proliferating CD4(+) and CD8(+) T cells and further analysis revealed T helper 1 (Th 1) cell supremacy. The GL261 tumor cell line produced very low levels of PGE2 in vitro and co-staining at the tumor site demonstrated that a large fraction of the COX-2(+) cells were derived from CD45(+) immune cells and more specifically macrophages (F4/80(+) ), indicating that tumor-infiltrating immune cells constitute the primary source of COX-2 and PGE2 in this model. We conclude that intratumoral COX-2 inhibition potentiates GM-CSF immunotherapy against established brain tumors at substantially lower doses than systemic administration. These findings underscore the central role of targeting COX-2 during immunotherapy and implicate intratumoral COX-2 as the primary target. © 2013 Wiley Periodicals, Inc.}},
author = {{Eberstål, Sofia and Sandén, Emma and Fritzell, Sara and Darabi, Anna and Visse, Edward and Siesjö, Peter}},
issn = {{0020-7136}},
language = {{eng}},
number = {{11}},
pages = {{2748--2753}},
publisher = {{John Wiley & Sons Inc.}},
series = {{International Journal of Cancer}},
title = {{Intratumoral COX-2 inhibition enhances GM-CSF immunotherapy against established mouse GL261 brain tumors.}},
url = {{http://dx.doi.org/10.1002/ijc.28607}},
doi = {{10.1002/ijc.28607}},
volume = {{134}},
year = {{2014}},
}