Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Feb 21;494(7437):361-5.
doi: 10.1038/nature11824. Epub 2013 Feb 3.

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

Heidi Braumüller  1 , Thomas Wieder, Ellen Brenner, Sonja Aßmann, Matthias Hahn, Mohammed Alkhaled, Karin Schilbach, Frank Essmann, Manfred Kneilling, Christoph Griessinger, Felicia Ranta, Susanne Ullrich, Ralph Mocikat, Kilian Braungart, Tarun Mehra, Birgit Fehrenbacher, Julia Berdel, Heike Niessner, Friedegund Meier, Maries van den Broek, Hans-Ulrich Häring, Rupert Handgretinger, Leticia Quintanilla-Martinez, Falko Fend, Marina Pesic, Jürgen Bauer, Lars Zender, Martin Schaller, Klaus Schulze-Osthoff, Martin Röcken
Affiliations
Free article

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

Heidi Braumüller et al. Nature. .
Free article

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.

PubMed Disclaimer

Comment in

  • Tumour immunology: Give it a rest.
    Alderton GK. Alderton GK. Nat Rev Cancer. 2013 Mar;13(3):150. doi: 10.1038/nrc3474. Nat Rev Cancer. 2013. PMID: 23429733 No abstract available.
  • Tumour immunology: Give it a rest.
    Alderton GK. Alderton GK. Nat Rev Immunol. 2013 Mar;13(3):156-7. doi: 10.1038/nri3414. Nat Rev Immunol. 2013. PMID: 23435330 No abstract available.

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. J Clin Invest. 2010 Jun;120(6):1800-3 - PubMed
    1. Cell. 2011 Mar 4;144(5):646-74 - PubMed
    1. J Natl Cancer Inst. 1991 Jun 5;83(11):757-66 - PubMed
    1. Blood. 2009 Aug 20;114(8):1696-706 - PubMed
    1. N Engl J Med. 2008 Jun 19;358(25):2704-15 - PubMed

Publication types

MeSH terms