Journal
NATURE
Volume 494, Issue 7437, Pages 361-365Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature11824
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Funding
- Sander Stiftung [2005.043.2, 2005.043.3]
- Deutsche Krebshilfe [109037]
- IZKF-Promotionskolleg 'Molekulare Medizin' [1886-0-0, PK 2011-3, PK 2012-1]
- Deutsche Forschungsgemeinschaft [SFB 685, SFB 773, Wi 1279/3-1]
- German Federal Ministry of Education and Research (BMBF)
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Cancer control by adaptive immunity involves a number of defined death(1-8) and clearance(9-11) mechanisms. However, efficient inhibition of exponential cancer growth by T cells and interferon-gamma (IFN-gamma) requires additional undefined mechanisms that arrest cancer cell proliferation(1-5,12,13). Here we show that the combined action of the T-helper-1-cell cytokines IFN-gamma and tumour necrosis factor (TNF) directly induces permanent growth arrest in cancers. To safely separate senescence induced by tumour immunity from oncogene-induced senescence(9-11,14-17), 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(18,19). When combined, IFN-gamma 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-gamma- and TNFR1-dependent senescence. Conversely, Tnfr1(-/-) Tag-expressing cancers resist cytokine-induced senescence and grow aggressively, even in TNFR1-expressing hosts. Finally, as IFN-gamma and TNF induce senescence in numerous murine and human cancers, this may be a general mechanism for arresting cancer progression.
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