Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold
Publication date
2019-07-25
Authors
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
Editors
Advisors
Supervisors
Document Type
Article
Metadata
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License
taverne
Abstract
New opportunities are needed to increase immune checkpoint blockade (ICB) impact for cancer patients. A genome-wide CRISPR/Cas9 screen uncovered several hits in the TNF pathway sensitizing tumor cells to T cell elimination. TNF antitumor activity was generally limited in tumors at baseline and in ICB non-responders, correlating with its low abundance. Selective inactivation of TNF signaling lowered melanoma and lung cancer thresholds to low TNF levels, thereby increasing tumor susceptibility to T cell attack and augmenting benefit from anti-PD-1 treatment.
Keywords
birinapant, immune checkpoint blockade, immunotherapy, lung cancer, melanoma, TNF, TRAF2, Taverne, General Biochemistry,Genetics and Molecular Biology, SDG 3 - Good Health and Well-being
Citation
Vredevoogd, D W, Kuilman, T, Ligtenberg, M A, Boshuizen, J, Stecker, K E, de Bruijn, B, Krijgsman, O, Huang, X, Kenski, J C N, Lacroix, R, Mezzadra, R, Gomez-Eerland, R, Yildiz, M, Dagidir, I, Apriamashvili, G, Zandhuis, N, van der Noort, V, Visser, N L, Blank, C U, Altelaar, M, Schumacher, T N & Peeper, D S 2019, 'Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold', Cell, vol. 178, no. 3, pp. 585-599.e15. https://doi.org/10.1016/j.cell.2019.06.014