title: Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium.
abstract: TNF has remarkable antitumor activities; however, therapeutic applications have not been possible because of the systemic and lethal proinflammatory effects induced by TNF. Both the antitumor and inflammatory effects of TNF are mediated by the TNF receptor p55 (p55TNFR) (encoded by the Tnfrsf1a gene). The antitumor effect stems from an induction of cell death in tumor endothelium, but the cell type that initiates the lethal inflammatory cascade has been unclear. Using conditional Tnfrsf1a knockout or reactivation mice, we found that the expression level of p55TNFR in intestinal epithelial cells (IECs) is a crucial determinant in TNF-induced lethal inflammation. Remarkably, tumor endothelium and IECs exhibited differential sensitivities to TNF when p55TNFR levels were reduced. Tumor-bearing Tnfrsf1a⁺⁺/⁻ or IEC-specific p55TNFR-deficient mice showed resistance to TNF-induced lethality, while the tumor endothelium remained fully responsive to TNF-induced apoptosis and tumors regressed. We demonstrate proof of principle for clinical application of this approach using neutralizing anti-human p55TNFR antibodies in human TNFRSF1A knockin mice. Our results uncover an important cellular basis of TNF toxicity and reveal that IEC-specific or systemic reduction of p55TNFR mitigates TNF toxicity without loss of antitumor efficacy.
authors.affiliation: Department for Molecular Biomedical Research, VIB, Ghent, Belgium.
authors.forename: Filip
authors.initials: F
authors.lastname: Van Hauwermeiren
authors.forename: Marietta
authors.initials: M
authors.lastname: Armaka
authors.forename: Niki
authors.initials: N
authors.lastname: Karagianni
authors.forename: Ksanthi
authors.initials: K
authors.lastname: Kranidioti
authors.forename: Roosmarijn E
authors.initials: RE
authors.lastname: Vandenbroucke
authors.forename: Sonja
authors.initials: S
authors.lastname: Loges
authors.forename: Maarten
authors.initials: M
authors.lastname: Van Roy
authors.forename: Jan
authors.initials: J
authors.lastname: Staelens
authors.forename: Leen
authors.initials: L
authors.lastname: Puimège
authors.forename: Ajay
authors.initials: A
authors.lastname: Palagani
authors.forename: Wim Vanden
authors.initials: WV
authors.lastname: Berghe
authors.forename: Panayiotis
authors.initials: P
authors.lastname: Victoratos
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Claude
authors.initials: C
authors.lastname: Libert
authors.forename: George
authors.initials: G
authors.lastname: Kollias
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D017209:Apoptosis; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004727:Endothelium / Q000473:pathology; D015870:Gene Expression; D055879:Gene Knock-In Techniques; D006801:Humans; D007249:Inflammation / Q000139:chemically induced; D007371:Interferon-gamma / Q000502:physiology; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D016207:Cytokines; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma