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Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium

(2013) JOURNAL OF CLINICAL INVESTIGATION. 123(6). p.2590-2603
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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.
Keywords
NF-KAPPA-B, IFN-GAMMA, TUMOR-NECROSIS-FACTOR, ANTIBODY-RESPONSES, INDUCED LETHALITY, INDUCED APOPTOSIS, RECOMBINANT HUMAN, FACTOR RECEPTOR-1, INTERFERON-GAMMA, MICE

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Chicago
Van Hauwermeiren, Filip, Marietta Armaka, Niki Karagianni, Ksanthi Kranidioti, Roosmarijn Vandenbroucke, Sonja Loges, Maarten Van Royen, et al. 2013. “Safe TNF-based Antitumor Therapy Following p55TNFR Reduction in Intestinal Epithelium.” Journal of Clinical Investigation 123 (6): 2590–2603.
APA
Van Hauwermeiren, F., Armaka, M., Karagianni, N., Kranidioti, K., Vandenbroucke, R., Loges, S., Van Royen, M., et al. (2013). Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium. JOURNAL OF CLINICAL INVESTIGATION, 123(6), 2590–2603.
Vancouver
1.
Van Hauwermeiren F, Armaka M, Karagianni N, Kranidioti K, Vandenbroucke R, Loges S, et al. Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium. JOURNAL OF CLINICAL INVESTIGATION. 2013;123(6):2590–603.
MLA
Van Hauwermeiren, Filip, Marietta Armaka, Niki Karagianni, et al. “Safe TNF-based Antitumor Therapy Following p55TNFR Reduction in Intestinal Epithelium.” JOURNAL OF CLINICAL INVESTIGATION 123.6 (2013): 2590–2603. Print.
@article{4106418,
  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.},
  author       = {Van Hauwermeiren, Filip and Armaka, Marietta and Karagianni, Niki and Kranidioti, Ksanthi and Vandenbroucke, Roosmarijn and Loges, Sonja and Van Royen, Maarten and Staelens, Jan and Puim{\`e}ge, Leen and Palagani, Ajay and Vanden Berghe, Wim and Victoratos, Panayiotis and Carmeliet, Peter and Libert, Claude and Kollias, George},
  issn         = {0021-9738},
  journal      = {JOURNAL OF CLINICAL INVESTIGATION},
  keyword      = {NF-KAPPA-B,IFN-GAMMA,TUMOR-NECROSIS-FACTOR,ANTIBODY-RESPONSES,INDUCED LETHALITY,INDUCED APOPTOSIS,RECOMBINANT HUMAN,FACTOR RECEPTOR-1,INTERFERON-GAMMA,MICE},
  language     = {eng},
  number       = {6},
  pages        = {2590--2603},
  title        = {Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium},
  url          = {http://dx.doi.org/10.1172/JCI65624},
  volume       = {123},
  year         = {2013},
}

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