Intratumoral COX‐2 inhibition enhances GM‐CSF immunotherapy against established mouse GL261 brain tumors

• Published in: International journal of cancer Vol. 134; no. 11; pp. 2748 - 2753
• Main Authors: Eberstål, Sofia, Sandén, Emma, Fritzell, Sara, Darabi, Anna, Visse, Edward, Siesjö, Peter
• Format: Journal Article
• Language: English
• Published: Hoboken, NJ Wiley-Blackwell 01-06-2014; Wiley Subscription Services, Inc
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols; Biological and medical sciences; Brain cancer; Brain Neoplasms - immunology; Brain Neoplasms - metabolism; Brain Neoplasms - therapy; brain tumor; Cancer; Cancer and Oncology; Cancer och onkologi; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Cell Proliferation; Clinical Medicine; COX‐2 inhibition; Cyclooxygenase 2 - chemistry; Cyclooxygenase 2 - metabolism; Cyclooxygenase 2 Inhibitors - therapeutic use; Dinoprostone - metabolism; Drug Synergism; Female; Flow Cytometry; Glioma - immunology; Glioma - metabolism; Glioma - therapy; GM‐CSF; Granulocyte-Macrophage Colony-Stimulating Factor - therapeutic use; Immunoenzyme Techniques; Immunotherapy; Intramolecular Oxidoreductases - metabolism; Isoxazoles - therapeutic use; Klinisk medicin; Medical and Health Sciences; Medical research; Medical sciences; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neurology; Prostaglandin-E Synthases; Rodents; Sulfonamides - therapeutic use; Tumor Cells, Cultured; Tumors; Tumors of the nervous system. Phacomatoses; Cyclooxygenase 2; Malignant glioma; Cancerology; GM-CSF; Immunotherapy; Established cell line; Inhibition; Nervous system diseases; Enzyme; Rodentia; COX-2 inhibition; brain tumor; Malignant tumor; Intracranial tumor; Cerebral disorder; Vertebrata; Mammalia; Treatment; Mouse; Animal; Central nervous system disease; Inhibitor; Oxidoreductases; Granulocyte macrophage colony stimulating factor; Cancer; immunotherapy
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.28607

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 (Th1) 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.
What's new?
Malignant brain tumors have a very poor prognosis and are targeted by immunotherapy, but efforts are thwarted by the pronounced immunosuppression induced by the tumors. Here, the authors combine immunotherapy with cyclooxygenase‐2 (COX‐2) inhibitors suppressing the production of a key immunosuppressive mediator, prostaglandin E2. Intratumoral application of a COX‐2 inhibitor enhanced the systemic T cell response against established gliomas when immunized with granulocyte macrophage colony stimulating factor‐secreting tumor cells and enhanced the cure rate in mice. The current results point to the tumor microenvironment as the major source of prostaglandins and uncover the therapeutic potential of enhanced immunotherapy in the treatment of malignant brain tumors.