| Literature DB >> 31303383 |
David W Vredevoogd1, Thomas Kuilman1, Maarten A Ligtenberg1, Julia Boshuizen1, Kelly E Stecker2, Beaunelle de Bruijn1, Oscar Krijgsman1, Xinyao Huang1, Juliana C N Kenski1, Ruben Lacroix1, Riccardo Mezzadra1, Raquel Gomez-Eerland1, Mete Yildiz1, Ilknur Dagidir1, Georgi Apriamashvili1, Nordin Zandhuis1, Vincent van der Noort3, Nils L Visser1, Christian U Blank4, Maarten Altelaar5, Ton N Schumacher1, Daniel S Peeper6.
Abstract
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.Entities:
Keywords: TNF; TRAF2; birinapant; immune checkpoint blockade; immunotherapy; lung cancer; melanoma
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Year: 2019 PMID： 31303383 DOI： 10.1016/j.cell.2019.06.014
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582