Intratumoral COX-2 Inhibition Enhances GM-CSF Immunotherapy Against Established Mouse GL261 Brain Tumors

Int J Cancer. 2014 Jun 1;134(11):2748-53. doi: 10.1002/ijc.28607. Epub 2013 Nov 25.

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.

Keywords: COX-2 inhibition; GM-CSF; brain tumor; immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols
  • Brain Neoplasms / immunology
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / therapy*
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Proliferation
  • Cyclooxygenase 2 / chemistry*
  • Cyclooxygenase 2 / metabolism
  • Cyclooxygenase 2 Inhibitors / therapeutic use*
  • Dinoprostone / metabolism
  • Drug Synergism
  • Female
  • Flow Cytometry
  • Glioma / immunology
  • Glioma / metabolism
  • Glioma / therapy*
  • Granulocyte-Macrophage Colony-Stimulating Factor / therapeutic use*
  • Immunoenzyme Techniques
  • Immunotherapy*
  • Intramolecular Oxidoreductases / metabolism
  • Isoxazoles / therapeutic use
  • Mice
  • Mice, Inbred C57BL
  • Prostaglandin-E Synthases
  • Sulfonamides / therapeutic use
  • Tumor Cells, Cultured

Substances

  • Cyclooxygenase 2 Inhibitors
  • Isoxazoles
  • Sulfonamides
  • valdecoxib
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • parecoxib
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • Intramolecular Oxidoreductases
  • Prostaglandin-E Synthases
  • Dinoprostone