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

Nature. 2013 Feb 21;494(7437):361-5. doi: 10.1038/nature11824. Epub 2013 Feb 3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Polyomavirus Transforming / genetics
  • Antigens, Polyomavirus Transforming / metabolism
  • Cell Cycle
  • Cell Proliferation
  • Cellular Senescence / immunology*
  • Cyclin-Dependent Kinase Inhibitor p16 / deficiency
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Cytokines / immunology*
  • Disease Models, Animal
  • Disease Progression
  • Female
  • Humans
  • Interferon-gamma / immunology
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mice, Transgenic
  • Neoplasms / immunology*
  • Neoplasms / pathology*
  • Oncogenes / genetics
  • Phosphoserine / metabolism
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Retinoblastoma Protein / chemistry
  • Retinoblastoma Protein / metabolism
  • STAT1 Transcription Factor / metabolism
  • Th1 Cells / immunology*
  • Time Factors
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Suppressor Protein p53 / metabolism


  • Antigens, Polyomavirus Transforming
  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cytokines
  • Receptors, Tumor Necrosis Factor, Type I
  • Retinoblastoma Protein
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Tnfrsf1a protein, mouse
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Protein p53
  • Phosphoserine
  • Interferon-gamma