Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold
| Autor: | Vredevoogd, David W., Kuilman, Thomas, Ligtenberg, Maarten A., Boshuizen, Julia, Stecker, Kelly E., de Bruijn, Beaunelle, Krijgsman, Oscar, Huang, Xinyao, Kenski, Juliana C.N., Lacroix, Ruben, Mezzadra, Riccardo, Gomez-Eerland, Raquel, Yildiz, Mete, Dagidir, Ilknur, Apriamashvili, Georgi, Zandhuis, Nordin, van der Noort, Vincent, Visser, Nils L., Blank, Christian U., Altelaar, Maarten, Schumacher, Ton N., Peeper, Daniel S., Afd Biomol.Mass Spect. and Proteomics, Sub Analysis begr. 01-01-2014, Inorganic Chemistry and Catalysis, Biomolecular Mass Spectrometry and Proteomics |
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| Přispěvatelé: | Afd Biomol.Mass Spect. and Proteomics, Sub Analysis begr. 01-01-2014, Inorganic Chemistry and Catalysis, Biomolecular Mass Spectrometry and Proteomics |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
TRAF2 medicine.medical_treatment TNF Apoptosis Kaplan-Meier Estimate CD8-Positive T-Lymphocytes Biochemistry Inhibitor of Apoptosis Proteins Mice 0302 clinical medicine Interferon Neoplasms Taverne Cytotoxicity Receptors Interferon 0303 health sciences Melanoma birinapant Receptor-Interacting Protein Serine-Threonine Kinases Tumor necrosis factor alpha Immunotherapy immunotherapy medicine.drug RNA Guide Kinetoplastida Signal Transduction Biology General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Interferon-gamma Cell Line Tumor medicine melanoma Animals Humans 030304 developmental biology Tumor Necrosis Factor-alpha Biochemistry Genetics and Molecular Biology(all) immune checkpoint blockade medicine.disease TNF Receptor-Associated Factor 2 Immune checkpoint Mice Inbred C57BL lung cancer Cancer research 030217 neurology & neurosurgery Genetics and Molecular Biology(all) Genetic screen |
| Zdroj: | Cell, 178(3), 585. Cell Press |
| ISSN: | 0092-8674 |
| Popis: | New opportunities are needed to increase immune checkpoint blockade (ICB) benefit. Whereas the interferon (IFN)γ pathway harbors both ICB resistance factors and therapeutic opportunities, this has not been systematically investigated for IFNγ-independent signaling routes. A genome-wide CRISPR/Cas9 screen to sensitize IFNγ receptor-deficient tumor cells to CD8 T cell elimination uncovered several hits mapping to the tumor necrosis factor (TNF) pathway. Clinically, we show that TNF antitumor activity is only limited in tumors at baseline and in ICB non-responders, correlating with its low abundance. Taking advantage of the genetic screen, we demonstrate that ablation of the top hit, TRAF2, lowers the TNF cytotoxicity threshold in tumors by redirecting TNF signaling to favor RIPK1-dependent apoptosis. TRAF2 loss greatly enhanced the therapeutic potential of pharmacologic inhibition of its interaction partner cIAP, another screen hit, thereby cooperating with ICB. Our results suggest that selective reduction of the TNF cytotoxicity threshold increases the susceptibility of tumors to immunotherapy. |
| Databáze: | OpenAIRE |
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