Inhibition of cyclooxygenase-2 Enhances Immunotherapy Against Experimental Brain Tumors

Cancer Immunol Immunother. 2012 Aug;61(8):1191-9. doi: 10.1007/s00262-011-1196-y. Epub 2012 Jan 3.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Neoplasms / enzymology
  • Brain Neoplasms / immunology
  • Brain Neoplasms / therapy
  • Combined Modality Therapy
  • Cyclooxygenase 2 / metabolism*
  • Cyclooxygenase 2 Inhibitors / pharmacology*
  • Disease Models, Animal
  • Flow Cytometry
  • Glioblastoma / enzymology
  • Glioblastoma / immunology
  • Glioblastoma / therapy*
  • Immunohistochemistry
  • Immunotherapy, Adoptive / methods*
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / immunology
  • Isoxazoles / pharmacology
  • Male
  • Neoplasms, Experimental / enzymology*
  • Neoplasms, Experimental / immunology
  • Neoplasms, Experimental / therapy*
  • Rats
  • Rats, Inbred F344

Substances

  • Cyclooxygenase 2 Inhibitors
  • Isoxazoles
  • Interferon-gamma
  • parecoxib
  • Cyclooxygenase 2