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 6

Increased MTD and anticancer effects in Tnfrsf1a+/– mice.

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Increased MTD and anticancer effects in Tnfrsf1a+/– mice. Antitumor ef...
Antitumor effect and survival after 10 days of high-dose TNF (50 μg/mouse) plus IFN-γ treatment (5,000 IU). (A) Toxicity of TNF plus IFN-γ in Tnfrsf1a+/+ mice (black triangles) and Tnfrsf1a+/– mice (blue circles). Healthy tumor-free mice (continuous line) and B16BL6 melanoma-bearing mice (dotted line) were injected daily with different doses of TNF plus IFN-γ for 10 days. Healthy mice were injected i.p., whereas tumor-bearing mice were injected s.c. paralesional. The horizontal line represents LD50. (B) B16BL6 melanoma-bearing Tnfrsf1a+/+, Tnfrsf1a+/–, and Tnfrsf1a–/– mice were treated daily by paralesional s.c. injection with PBS (white symbols; Tnfrsf1a+/+, n = 5; Tnfrsf1a+/–, n = 3; Tnfrsf1a–/–, n = 4) or high-dose TNF (black symbols; Tnfrsf1a+/+, n = 6; Tnfrsf1a+/–, n = 10; Tnfrsf1a–/–, n = 6) plus IFN-γ. Tnfrsf1a–/– mice had to be euthanized due to large tumor size (indicated by //). (C) LLC-bearing mice were treated daily with PBS (white symbols; Tnfrsf1a+/+, n = 6; Tnfrsf1a+/–, n = 9; Tnfrsf1a–/–, n = 4) or TNF/IFN-γ (black symbols; Tnfrsf1a+/+, n = 5; Tnfrsf1a+/–, n = 13; Tnfrsf1a–/–, n = 9). (D) B16BL6 melanoma-bearing Tnfrsf1afl/fl and Villin-Cre Tnfrsf1afl/fl mice were treated daily by paralesional injection of 12 mg TNF plus IFN-γ (5,000 IU) for 10 days (Tnfrsf1afl/fl, n = 20 and Villin-Cre Tnfrsf1afl/fl, n = 16). Tnfrsf1afl/fl PBS-treated mice (n = 11) had to be euthanized because of their large tumor size (indicated by //). Data represent mean ± SEM. *P < 0.05, ***P < 0.001, Student’s t test in B and C (left) and log-rank test (right); in tumor size index (TSI) graphs, compared with PBS- and TNF/IFN-γ–treated Tnfrsf1a+/– (A–C) or TNF/IFN-γ–treated Tnfrsf1afl/fl and Villin-Cre Tnfrsf1afl/fl (D).