title: Antisense oligonucleotides against TNFR1 prevent toxicity of TNF/IFNγ treatment in mouse tumor models.
abstract: Tumor necrosis factor (TNF) has remarkable antitumor effects, but its systemic therapeutic use is prevented by its lethal inflammatory effects. TNFR1 (P55) is essential for both the antitumor and toxic effects because both of them are absent in P55-deficient mice. In previous work we demonstrated that P55+/- mice are completely resistant to TNF toxicity, while the antitumor effects induced by TNF combined with interferon gamma (IFNγ) remain fully functional in these mice. Hence, a high dose of TNF/IFNγ has an excellent therapeutic potential when P55 levels are reduced, because TNF induces tumor regression without systemic toxicity. Here, we provide proof of principle for therapeutic application of this approach by using antisense oligonucleotides (ASOs). Treatment of mice with ASOs targeting P55 resulted in a strong reduction in P55 protein levels in liver, small intestine and blood mononuclear cells. This P55 downregulation was associated with significant protection of mice against acute TNF toxicity as measured by hypothermia, systemic inflammation and lethality. This treatment also protected mice against toxicity of TNF/IFNγ treatment in several cancer models: B16Bl6, Lewis lung carcinoma and a lung colony model. Our results confirm the therapeutic value of this strategy, which could lead to the development of a safer and more effective TNF/IFNγ antitumor therapy.
authors.affiliation: Inflammation Research Center (IRC), VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Filip
authors.initials: F
authors.lastname: Van Hauwermeiren
authors.forename: Roosmarijn E
authors.initials: RE
authors.lastname: Vandenbroucke
authors.forename: Lynda
authors.initials: L
authors.lastname: Grine
authors.forename: Leen
authors.initials: L
authors.lastname: Puimège
authors.forename: Elien
authors.initials: E
authors.lastname: Van Wonterghem
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Claude
authors.initials: C
authors.lastname: Libert
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D007371:Interferon-gamma / Q000633:toxicity*; D007421:Intestine, Small / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D020714:Maximum Tolerated Dose; D008546:Melanoma, Experimental / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
chemical_list: D016376:Oligonucleotides, Antisense; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: TNF/IFNγ therapy; TNFR1; antisense oligonucleotides; toxicity