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 cyclooxygease-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 E2 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.
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Grossman SA, Ye X, Piantadosi S, Desideri S, Nabors LB, Rosenfeld M, Fisher J (2010) Survival of patients with newly diagnosed glioblastoma treated with radiation and temozolomide in research studies in the United States. Clin Cancer Res 16(8):2443–2449
De Vleeschouwer S, Fieuws S, Rutkowski S, Van Calenbergh F, Van Loon J, Goffin J, Sciot R, Wilms G, Demaerel P, Warmuth-Metz M, Soerensen N, Wolff JE, Wagner S, Kaempgen E, Van Gool SW (2008) Postoperative adjuvant dendritic cell-based immunotherapy in patients with relapsed glioblastoma multiforme. Clin Cancer Res 14(10):3098–3104
Wheeler CJ, Black KL (2009) DCVax-brain and DC vaccines in the treatment of GBM. Expert Opin Investig Drugs 18(4):509–519
Visse E, Siesjo P, Widegren B, Sjogren HO (1999) Regression of intracerebral rat glioma isografts by therapeutic subcutaneous immunization with interferon-gamma, interleukin-7, or B7–1-transfected tumor cells. Cancer Gene Ther 6(1):37–44
Janelidze S, Bexell D, Badn W, Darabi A, Smith KE, Fritzell S, Gunnarsson S, Milos P, Bengzon J, Salford LG, Siesjo P, Visse E (2009) Immunizations with IFN gamma secreting tumor cells can eliminate fully established and invasive rat gliomas. J Immunother 32(6):593–601
Wang L, Shi JS, van Ginkel FW, Lan LQ, Niemeyer G, Martin DR, Snyder EY, Cox NR (2009) Neural stem/progenitor cells modulate immune responses by suppressing T lymphocytes with nitric oxide and prostaglandin E2. Exp Neurol 216(1):177–183
Harris SG, Padilla J, Koumas L, Ray D, Phipps RP (2002) Prostaglandins as modulators of immunity. Trends Immunol 23(3):144–150
Shreedhar V, Giese T, Sung VW, Ullrich SE (1998) A cytokine cascade including prostaglandin E2, IL-4, and IL-10 is responsible for UV-induced systemic immune suppression. J Immunol 160(8):3783–3789
Huang M, Stolina M, Sharma S, Mao JT, Zhu L, Miller PW, Wollman J, Herschman H, Dubinett SM (1998) Non-small cell lung cancer cyclooxygenase-2-dependent regulation of cytokine balance in lymphocytes and macrophages: up-regulation of interleukin 10 and down-regulation of interleukin 12 production. Cancer Res 58(6):1208–1216
Baratelli F, Lin Y, Zhu L, Yang SC, Heuze-Vourc’h N, Zeng G, Reckamp K, Dohadwala M, Sharma S, Dubinett SM (2005) Prostaglandin E-2 induces FOXP3 gene expression and T regulatory cell function in human CD4(+) T cells. J Immunol 175(3):1483–1490
Park SW, Lee SG, Song SH, Heo DS, Park BJ, Lee DW, Kim KH, Sung MW (2003) The effect of nitric oxide on cyclooxygenase-2 (COX-2) overexpression in head and neck cancer cell lines. Int J Cancer 107(5):729–738
Kim SF, Huri DA, Snyder SH (2005) Inducible nitric oxide synthase binds, S-nitrosylates, and activates cyclooxygenase-2. Science 310(5756):1966–1970
von Bergwelt-Baildon MS, Popov A, Saric T, Chemnitz J, Classen S, Stoffel MS, Fiore F, Roth U, Beyer M, Debey S, Wickenhauser C, Hanisch FG, Schultze JL (2006) CD25 and indoleamine 2,3-dioxygenase are up-regulated by prostaglandin E2 and expressed by tumor-associated dendritic cells in vivo: additional mechanisms of T-cell inhibition. Blood 108(1):228–237
Rodriguez PC, Hernandez CP, Quiceno D, Dubinett SM, Zabaleta J, Ochoa JB, Gilbert J, Ochoa AC (2005) Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma. J Exp Med 202(7):931–939
Mandapathil M, Szczepanski MJ, Szajnik M, Ren J, Jackson EK, Johnson JT, Gorelik E, Lang S, Whiteside TL (2010) Adenosine and prostaglandin E2 cooperate in the suppression of immune responses mediated by adaptive regulatory T cells. J Biol Chem 285(36):27571–27580
Bergmann C, Strauss L, Zeidler R, Lang S, Whiteside TL (2007) Expansion of human T regulatory type 1 cells in the microenvironment of cyclooxygenase 2 overexpressing head and neck squamous cell carcinoma. Cancer Res 67(18):8865–8873
Toomey D, Conroy H, Jarnicki AG, Higgins SC, Sutton C, Mills KHG (2008) Therapeutic vaccination with dendritic cells pulsed with tumor-derived Hsp70 and a COX-2 inhibitor induces protective immunity against B16 melanoma. Vaccine 26(27–28):3540–3549
Dovedi SJ, Kirby JA, Davies BR, Leung H, Kelly JD (2008) Celecoxib has potent antitumour effects as a single agent and in combination with BCG immunotherapy in a model of urothelial cell carcinoma. Eur Urol 54(3):621–630
DeLong P, Tanaka T, Kruklitis R, Henry AC, Kapoor V, Kaiser LR, Sterman DH, Albelda SM (2003) Use of cyclooxygenase-2 inhibition to enhance the efficacy of immunotherapy. Cancer Res 63(22):7845–7852
Mukherjee P, Basu GD, Tinder TL, Subramani DB, Bradley JM, Arefayene M, Skaar T, De Petris G (2009) Progression of pancreatic adenocarcinoma is significantly impeded with a combination of vaccine and COX-2 inhibition. J Immunol 182(1):216–224
Hahn T, Alvarez I, Kobie JJ, Ramanathapuram L, Dial S, Fulton A, Besselsen D, Walker E, Akporiaye ET (2006) Short-term dietary administration of celecoxib enhances the efficacy of tumor lysate-pulsed dendritic cell vaccines in treating murine breast cancer. Int J Cancer 118(9):2220–2231
Hood WF, Gierse JK, Isakson PC, Kiefer JR, Kurumbail RG, Seibert K, Monahan JB (2003) Characterization of celecoxib and valdecoxib binding to cyclooxygenase. Mol Pharmacol 63(4):870–877
Teagarden DL, Nema S (2007) Case study: parecoxib: a prodrug of valdecoxib. In: Stella VJ, Borchardt RT, Hageman MJ, Oliyai R, Maag H, Tilley JW (eds) Prodrugs, vol V. Springer, New York, pp 1335–1346
Koppe MJ, Oyen WJ, Bleichrodt RP, Hendriks T, Verhofstad AA, Goldenberg DM, Boerman OC (2006) Combination therapy using the cyclooxygenase-2 inhibitor parecoxib and radioimmunotherapy in nude mice with small peritoneal metastases of colonic origin. Cancer Immunol Immunother 55(1):47–55
Schug SA, Joshi GP, Camu F, Pan S, Cheung R (2009) Cardiovascular safety of the cyclooxygenase-2 selective inhibitors parecoxib and valdecoxib in the postoperative setting: an analysis of integrated data. Anesth Analg 108(1):299–307
Badn W, Visse E, Darabi A, Smith KE, Salford LG, Siesjo P (2007) Postimmunization with IFN-gamma-secreting glioma cells combined with the inducible nitric oxide synthase inhibitor mercaptoethylguanidine prolongs survival of rats with intracerebral tumors. J Immunol 179(6):4231–4238
Siesjo P, Visse E, Lindvall M, Salford L, Sjogren HO (1993) Immunization with mutagen-treated (Tum-) cells causes rejection of nonimmunogenic rat glioma isografts. Cancer Immunol Immunother 37(1):67–74
Joki T, Heese O, Nikas DC, Bello L, Zhang J, Kraeft SK, Seyfried NT, Abe T, Chen LB, Carroll RS, Black PM (2000) Expression of cyclooxygenase 2 (COX-2) in human glioma and in vitro inhibition by a specific COX-2 inhibitor, NS-398. Cancer Res 60(17):4926–4931
Lalier L, Cartron PF, Pedelaborde F, Olivier C, Loussouarn D, Martin SA, Meflah K, Menanteau J, Vallette FM (2007) Increase in PGE2 biosynthesis induces a Bax dependent apoptosis correlated to patients’ survival in glioblastoma multiforme. Oncogene 26(34):4999–5009
Hara A, Okayasu I (2004) Cyclooxygenase-2 and inducible nitric oxide synthase expression in human astrocytic gliomas: correlation with angiogenesis and prognostic significance. Acta Neuropathol 108(1):43–48
Shono T, Tofilon PJ, Bruner JM, Owolabi O, Lang FF (2001) Cyclooxygenase-2 expression in human gliomas: prognostic significance and molecular correlations. Cancer Res 61(11):4375–4381
Janabi N, Jensen PN, Major EO (2004) Differential effects of interferon-gamma on the expression of cyclooxygenase-2 in high-grade human gliomas versus primary astrocytes. J Neuroimmunol 156(1–2):113–122
Klampfer L, Huang J, Kaler P, Sasazuki T, Shirasawa S, Augenlicht L (2007) STAT1-independent inhibition of cyclooxygenase-2 expression by IFNgamma; a common pathway of IFNgamma-mediated gene repression but not gene activation. Oncogene 26(14):2071–2081
Akasaki Y, Liu G, Chung NH, Ehtesham M, Black KL, Yu JS (2004) Induction of a CD4+ T regulatory type 1 response by cyclooxygenase-2-overexpressing glioma. J Immunol 173(7):4352–4359
Nagamachi M, Sakata D, Kabashima K, Furuyashiki T, Murata T, Segi-Nishida E, Soontrapa K, Matsuoka T, Miyachi Y, Narumiya S (2007) Facilitation of Th1-mediated immune response by prostaglandin E receptor EP1. J Exp Med 204(12):2865–2874
Yao C, Sakata D, Esaki Y, Li Y, Matsuoka T, Kuroiwa K, Sugimoto Y, Narumiya S (2009) Prostaglandin E2-EP4 signaling promotes immune inflammation through Th1 cell differentiation and Th17 cell expansion. Nat Med 15(6):633–640
Reding T, Bimmler D, Perren A, Sun LK, Fortunato F, Storni F, Graf R (2006) A selective COX-2 inhibitor suppresses chronic pancreatitis in an animal model (WBN/Kob rats): significant reduction of macrophage infiltration and fibrosis. Gut 55(8):1165–1173
Provinciali M, Argentati K, Tibaldi A (2000) Efficacy of cancer gene therapy in aging: adenocarcinoma cells engineered to release IL-2 are rejected but do not induce tumor specific immune memory in old mice. Gene Ther 7(7):624–632
Chen H, Paul WE (1997) Cultured NK1.1+ CD4+ T cells produce large amounts of IL-4 and IFN-gamma upon activation by anti-CD3 or CD1. J Immunol 159(5):2240–2249
Munder M, Mallo M, Eichmann K, Modolell M (1998) Murine macrophages secrete interferon gamma upon combined stimulation with interleukin (IL)-12 and IL-18: a novel pathway of autocrine macrophage activation. J Exp Med 187(12):2103–2108
Taieb J, Chaput N, Menard C, Apetoh L, Ullrich E, Bonmort M, Pequignot M, Casares N, Terme M, Flament C, Opolon P, Lecluse Y, Metivier D, Tomasello E, Vivier E, Ghiringhelli F, Martin F, Klatzmann D, Poynard T, Tursz T, Raposo G, Yagita H, Ryffel B, Kroemer G, Zitvogel L (2006) A novel dendritic cell subset involved in tumor immunosurveillance. Nat Med 12(2):214–219
Nemeth K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, Robey PG, Leelahavanichkul K, Koller BH, Brown JM, Hu X, Jelinek I, Star RA, Mezey E (2009) Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med 15(1):42–49
Fitzpatrick FA, Aguirre R, Pike JE, Lincoln FH (1980) The stability of 13,14-dihydro-15 keto-PGE2. Prostaglandins 19(6):917–931
Acknowledgments
We thank Catarina Blennow for her excellent technical support. This work was supported by the Children’s Cancer Foundation of Sweden, the Skane Region Funds, and the Hans and Märit Rausing Charitable Fund.
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The authors declare that they have no conflict of interest.
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Eberstål, S., Badn, W., Fritzell, S. et al. Inhibition of cyclooxygenase-2 enhances immunotherapy against experimental brain tumors. Cancer Immunol Immunother 61, 1191–1199 (2012). https://doi.org/10.1007/s00262-011-1196-y
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DOI: https://doi.org/10.1007/s00262-011-1196-y