Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold

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 s...

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Vydáno v:	Cell Ročník 178; číslo 3; s. 585
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 25.07.2019
Témata:	Animals Apoptosis - drug effects CD8-Positive T-Lymphocytes - cytology CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - metabolism Cell Line, Tumor Humans Immunotherapy Inhibitor of Apoptosis Proteins - metabolism Interferon gamma Receptor Interferon-gamma - metabolism Kaplan-Meier Estimate Male Mice Mice, Inbred C57BL Neoplasms - mortality Neoplasms - therapy Receptor-Interacting Protein Serine-Threonine Kinases - metabolism Receptors, Interferon - deficiency Receptors, Interferon - genetics RNA, Guide, CRISPR-Cas Systems - metabolism Signal Transduction - drug effects TNF Receptor-Associated Factor 2 - deficiency TNF Receptor-Associated Factor 2 - genetics Tumor Necrosis Factor-alpha - metabolism Tumor Necrosis Factor-alpha - pharmacology lung cancer immunotherapy melanoma TRAF2 birinapant TNF immune checkpoint blockade
ISSN:	1097-4172, 1097-4172
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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4172 1097-4172
DOI:	10.1016/j.cell.2019.06.014