Inhibition of cyclooxygenase-2 enhances immunotherapy against experimental brain tumors

• DOI: 10.1007/s00262-011-1196-y
• Publication Date: 2012-01-02T10:42:34Z
• Authors: Sofia Eberstål; Wiaam Badn; Sara Fritzell; Magnus Esbjörnsson; Anna Darabi; Edward Visse; Peter Siesjö
• Keywords: Male; 0301 basic medicine; Cyclooxygenase 2 Inhibitors; Brain Neoplasms; Isoxazoles; Neoplasms, Experimental; Flow Cytometry; Combined Modality Therapy; Immunohistochemistry; Immunotherapy, Adoptive; Rats, Inbred F344; Rats; 3. Good health; Disease Models, Animal; Interferon-gamma; 03 medical and health sciences; Cyclooxygenase 2; Cancer and Oncology; Animals; Glioblastoma

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.