Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium
Filip Van Hauwermeiren, … , Claude Libert, George Kollias
Filip Van Hauwermeiren, … , Claude Libert, George Kollias
Published May 15, 2013
Citation Information: J Clin Invest. 2013;123(6):2590-2603. https://doi.org/10.1172/JCI65624.
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Research Article Oncology

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

Filip Van Hauwermeiren, Marietta Armaka, Niki Karagianni, Ksanthi Kranidioti, Roosmarijn E. Vandenbroucke, Sonja Loges, Maarten Van Roy, Jan Staelens, Leen Puimège, Ajay Palagani, Wim Vanden Berghe, Panayiotis Victoratos, Peter Carmeliet, Claude Libert, George Kollias

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Figure 1

Resistance of Tnfrsf1a+/– mice to TNF-induced lethal inflammation.

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Resistance of Tnfrsf1a+/– mice to TNF-induced lethal inflammation. (A)...
(A) Serum IL-6 6 hours after a single i.p. injection of 100 μg TNF in the Rothe (12), Pfeffer (14), and Peschon (13) Tnfrsf1a-deficient mouse lines. ***P < 0.001, compared with Tnfrsf1a+/+. (B) Body temperature (***P < 0.001, compared with Tnfrsf1a+/– and Tnfrsf1a–/–), (C) sickness score, (D) serum AST and ALT levels, and (E) intestinal permeability of Tnfrsf1a+/+, Tnfrsf1a+/–, and Tnfrsf1a–/– mice after i.p injection with 50 μg TNF i.p. (or 25 μg i.p. for permeability assay) (n = 8 for all groups). (F) p55TNFR expression, measured by ELISA, in liver samples. (G) Specific binding of 125I-hTNF to BMDMs. In D and F, levels in Tnfrsf1a–/– and Tnfrsf1a+/– were 0, so no statistical significance could be calculated toward Tnfrsf1a+/+ data. Data represent mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 (Student’s t test).