T-helper-1-cell cytokines drive cancer into senescence
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- 3 February 2013
- journal article
- letter
- Published by Springer Science and Business Media LLC in Nature
- Vol. 494 (7437), 361-365
- https://doi.org/10.1038/nature11824
Abstract
Cancer control by adaptive immunity involves a number of defined death1,2,3,4,5,6,7,8 and clearance9,10,11 mechanisms. However, efficient inhibition of exponential cancer growth by T cells and interferon-γ (IFN-γ) requires additional undefined mechanisms that arrest cancer cell proliferation1,2,3,4,5,12,13. 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 senescence9,10,11,14,15,16,17, 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 control18,19. 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.Keywords
This publication has 43 references indexed in Scilit:
- gp100 Peptide Vaccine and Interleukin-2 in Patients with Advanced MelanomaNew England Journal of Medicine, 2011
- Hallmarks of Cancer: The Next GenerationCell, 2011
- CD4+ T Cells Contribute to the Remodeling of the Microenvironment Required for Sustained Tumor Regression upon Oncogene InactivationCancer Cell, 2010
- Improved Survival with Ipilimumab in Patients with Metastatic MelanomaNew England Journal of Medicine, 2010
- Senescence in tumours: evidence from mice and humansNature Reviews Cancer, 2010
- Impaired interferon signaling is a common immune defect in human cancerProceedings of the National Academy of Sciences of the United States of America, 2009
- Treatment of Metastatic Melanoma with Autologous CD4+ T Cells against NY-ESO-1New England Journal of Medicine, 2008
- Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomasNature, 2007
- Cancer Regression in Patients After Transfer of Genetically Engineered LymphocytesScience, 2006
- Probing tumor phenotypes using stable and regulated synthetic microRNA precursorsNature Genetics, 2005