Inhibition of cyclooxygenase-2 enhances immunotherapy against experimental brain tumors.
Glioblastoma multiforme is the most common and aggressive malignant brain tumor in humans, and the prognosis is very poor despite conventional therapy. Immunotherapy represents a novel treatment approach, but the effect is often weakened by release of immune-suppressive molecules such as prostaglandins. In the current study, we investigated the effect of immunotherapy with irradiated interferon-γ (IFN-γ)-secreting tumor cells and administration of the selective cyclooxygenase-2 (COX-2) inhibitor parecoxib as treatment of established rat brain tumors. COX-2 inhibition and immunotherapy significantly enhanced the long-term cure rate (81% survival) compared with immunotherapy alone (19% survival), and there was a significant increase in plasma IFN-γ levels in animals treated with the combined therapy, suggesting a systemic T helper 1 immune response. COX-2 inhibition alone, however, did neither induce cure nor prolonged survival. The tumor cells were identified as the major source of COX-2 both in vivo and in vitro, and unmodified tumor cells produced prostaglandin E(2) in vitro, while the IFN-γ expressing tumor cells secreted significantly lower levels. In conclusion, we show that immunotherapy of experimental brain tumors is greatly potentiated when combined with COX-2 inhibition. Based on our results, the clinically available drug parecoxib may be added to immunotherapy against human brain tumors. Furthermore, the discovery that IFN-γ plasma levels can be used to determine the ongoing in vivo immune response has translational potential.
Glioma Immunotherapy Group, The Rausing Laboratory, BMC D14, Divison of Neurosurgery, Department of Clinical Sciences, Lund University, Lund, Sweden. sofia.eberstal@med.lu.se
Sofia
S
Eberstål
Wiaam
W
Badn
Sara
S
Fritzell
Magnus
M
Esbjörnsson
Anna
A
Darabi
Edward
E
Visse
Peter
P
Siesjö
D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology / Q000276:immunology / Q000628:therapy; D003131:Combined Modality Therapy; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005909:Glioblastoma / Q000201:enzymology / Q000276:immunology / Q000628:therapy*; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D009374:Neoplasms, Experimental / Q000201:enzymology* / Q000276:immunology / Q000628:therapy*; D051381:Rats; D011916:Rats, Inbred F344
D052246:Cyclooxygenase 2 Inhibitors; D007555:Isoxazoles; D007371:Interferon-gamma; C409945:parecoxib; D051546:Cyclooxygenase 2