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Intratumoral COX-2 inhibition enhances GM-CSF immunotherapy against established mouse GL261 brain tumors.
Int J Cancer. 2014 Jun 01; 134(11):2748-53.IJ

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 antitumor 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 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.

Authors+Show Affiliations

Glioma Immunotherapy Group, Division of Neurosurgery, Department of Clinical Sciences, Lund University, Lund, Sweden.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24243648

Citation

Eberstål, Sofia, et al. "Intratumoral COX-2 Inhibition Enhances GM-CSF Immunotherapy Against Established Mouse GL261 Brain Tumors." International Journal of Cancer, vol. 134, no. 11, 2014, pp. 2748-53.
Eberstål S, Sandén E, Fritzell S, et al. Intratumoral COX-2 inhibition enhances GM-CSF immunotherapy against established mouse GL261 brain tumors. Int J Cancer. 2014;134(11):2748-53.
Eberstål, S., Sandén, E., Fritzell, S., Darabi, A., Visse, E., & Siesjö, P. (2014). Intratumoral COX-2 inhibition enhances GM-CSF immunotherapy against established mouse GL261 brain tumors. International Journal of Cancer, 134(11), 2748-53. https://doi.org/10.1002/ijc.28607
Eberstål S, et al. Intratumoral COX-2 Inhibition Enhances GM-CSF Immunotherapy Against Established Mouse GL261 Brain Tumors. Int J Cancer. 2014 Jun 1;134(11):2748-53. PubMed PMID: 24243648.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Intratumoral COX-2 inhibition enhances GM-CSF immunotherapy against established mouse GL261 brain tumors. AU - Eberstål,Sofia, AU - Sandén,Emma, AU - Fritzell,Sara, AU - Darabi,Anna, AU - Visse,Edward, AU - Siesjö,Peter, Y1 - 2013/11/25/ PY - 2013/05/21/received PY - 2013/10/18/accepted PY - 2013/11/19/entrez PY - 2013/11/19/pubmed PY - 2014/5/23/medline KW - COX-2 inhibition KW - GM-CSF KW - brain tumor KW - immunotherapy SP - 2748 EP - 53 JF - International journal of cancer JO - Int. J. Cancer VL - 134 IS - 11 N2 - 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 antitumor 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 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. SN - 1097-0215 UR - https://www.unboundmedicine.com/medline/citation/24243648/Intratumoral_COX_2_inhibition_enhances_GM_CSF_immunotherapy_against_established_mouse_GL261_brain_tumors_ L2 - https://doi.org/10.1002/ijc.28607 DB - PRIME DP - Unbound Medicine ER -