Abstract：
: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.
journal_name
Naturejournal_title
Natureauthors
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,doi
10.1038/nature11824subject
Has Abstractpub_date
2013-02-21 00:00:00pages
361-5issue
7437eissn
0028-0836issn
1476-4687pii
nature11824journal_volume
494pub_type
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