Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold

David W. Vredevoogd, Thomas Kuilman, Maarten A. Ligtenberg, Julia Boshuizen, Kelly E. Stecker, Beaunelle de Bruijn, Oscar Krijgsman, Xinyao Huang, Juliana C. N. Kenski, Ruben Lacroix, Riccardo Mezzadra, Raquel Gomez-Eerland, Mete Yildiz, Ilknur Dagidir, Georgi Apriamashvili, Nordin Zandhuis, Vincent van der Noort, Nils L. Visser, Christian U. Blank, Maarten AltelaarTon N. Schumacher, Daniel S. Peeper

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Pages (from-to)585-599.e15
JournalCell
Volume178
Issue number3
DOIs
Publication statusPublished - 25 Jul 2019
Externally publishedYes

Cite this

Vredevoogd, D. W., Kuilman, T., Ligtenberg, M. A., Boshuizen, J., Stecker, K. E., de Bruijn, B., ... Peeper, D. S. (2019). Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold. Cell, 178(3), 585-599.e15. https://doi.org/10.1016/j.cell.2019.06.014