학술논문
TNFR2/BIRC3-TRAF1 signaling pathway as a novel NK cell immune checkpoint in cancer
Document Type
article
Author
Alexandre Ivagnès; Meriem Messaoudene; Gautier Stoll; Bertrand Routy; Aurélie Fluckiger; Takahiro Yamazaki; Kristina Iribarren; Connie P. M. Duong; Laetitia Fend; Anne Caignard; Isabelle Cremer; Axel LeCesne; Julien Adam; Charles Honoré; Olivier Mir; Loïc Chaigneau; Anne Berger; Pierre Validire; Christos Christidis; Valérie Le Brun-Ly; Mark J. Smyth; Xavier Mariette; Benoît L. Salomon; Guido Kroemer; Sylvie Rusakiewicz; Laurence Zitvogel
Source
OncoImmunology, Vol 7, Iss 12 (2018)
Subject
Language
English
ISSN
2162-402X
2162402X
2162402X
Abstract
Natural Killer (NK) cells control metastatic dissemination of murine tumors and are an important prognostic factor in several human malignancies. However, tumor cells hijack many of the NK cell functional features compromising their tumoricidal activity. Here, we show a deleterious role of the TNFα/TNFR2/BIRC3/TRAF1 signaling cascade in NK cells from the tumor microenvironment (TME). TNFα induces BIRC3/cIAP2 transcripts and reduces NKp46/NCR1 transcription and surface expression on NK cells, promoting metastases dissemination in mice and poor prognosis in GIST patients. NKp30 engagement, by promoting the release of TNFα, also contributes to BIRC3 upregulation, and more so in patients expressing predominantly NKp30C isoforms. These findings reveal that in the absence of IL-12 or a Th1-geared TME, TNFα can be considered as a negative regulatory cytokine for innate effectors.