PuSH - Publication Server of Helmholtz Zentrum München

Braumüller, H.* ; Wieder, T.* ; Brenner, E.* ; Aßmann, S.* ; Hahn, M.* ; Alkhaled, M.* ; Schilbach, K.* ; Essmann, F.* ; Kneilling, M.* ; Griessinger, C.* ; Ranta, F.* ; Ullrich, S.* ; Mocikat, R. ; Braungart, K.* ; Mehra, T.* ; Fehrenbacher, B.* ; Berdel, J.* ; Niessner, H.* ; Meier, F.* ; van den Broek, M.* ; Häring, H.-U.* ; Handgretinger, R.* ; Quintanilla-Martinez, L.* ; Fend, F.* ; Pesic, M.* ; Bauer, J.* ; Zender, L.* ; Schaller, M.* ; Schulze-Osthoff, K.* ; Röcken, M.*

T-helper-1-cell cytokines drive cancer into senescence.

Nature 494, 361-365 (2013)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
Cancer control by adaptive immunity involves a number of defined death and clearance mechanisms. However, efficient inhibition of exponential cancer growth by T cells and interferon-γ (IFN-γ) requires additional undefined mechanisms that arrest cancer cell proliferation. Here we show that the combined action of the T-helper-1-cell cytokines IFN-γ and tumour necrosis factor (TNF) directly induces permanent growth arrest in cancers. To safely separate senescence induced by tumour immunity from oncogene-induced senescence, we used a mouse model in which the Simian virus 40 large T antigen (Tag) expressed under the control of the rat insulin promoter creates tumours by attenuating p53- and Rb-mediated cell cycle control. When combined, IFN-γ and TNF drive Tag-expressing cancers into senescence by inducing permanent growth arrest in G1/G0, activation of p16INK4a (also known as CDKN2A), and downstream Rb hypophosphorylation at serine 795. This cytokine-induced senescence strictly requires STAT1 and TNFR1 (also known as TNFRSF1A) signalling in addition to p16INK4a. In vivo, Tag-specific T-helper 1 cells permanently arrest Tag-expressing cancers by inducing IFN-γ- and TNFR1-dependent senescence. Conversely, Tnfr1(-/- )Tag-expressing cancers resist cytokine-induced senescence and grow aggressively, even in TNFR1-expressing hosts. Finally, as IFN-γ and TNF induce senescence in numerous murine and human cancers, this may be a general mechanism for arresting cancer progression.
Altmetric
Additional Metrics?
[➜Log in]
Edit extra informations Login
Publication type Article: Journal article
Document type Scientific Article
Keywords Oncogene-induced Senescence ; Cd4(+) T-cells ; Multistage Carcinogenesis ; Tumor Dormancy ; Mice ; Surveillance ; Regression ; Melanoma ; Pathway ; P53
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Journal Nature
Quellenangaben Volume: 494, Issue: 7437, Pages: 361-365 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Molecular Immunology (IMI)