生物
肿瘤坏死因子α
癌症研究
免疫疗法
细胞毒性
交通2
干扰素
CD8型
清脆的
封锁
细胞凋亡
免疫学
免疫系统
受体
遗传学
肿瘤坏死因子受体
基因
体外
作者
David W. Vredevoogd,Thomas Kuilman,Maarten A. Ligtenberg,Julia Boshuizen,Kelly E. Stecker,Beaunelle de Bruijn,Oscar Krijgsman,Xinyao Huang,Juliana Kenski,Ruben Lacroix,Riccardo Mezzadra,Raquel Gomez-Eerland,Ufuk Yıldız,Ilknur Dagidir,Georgi Apriamashvili,Nordin D. Zandhuis,Vincent van der Noort,Nils L. Visser,Christian U. Blank,Maarten Altelaar,Ton N. Schumacher,Daniel S. Peeper
出处
期刊:Cell
[Elsevier]
日期:2019-07-01
卷期号:178 (3): 585-599.e15
被引量:189
标识
DOI:10.1016/j.cell.2019.06.014
摘要
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.
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