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

Nature volume 494, pages 361–365 (2013)Cite this article

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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.

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Figure 1: Combined, the TH1 cytokines IFN-γ and TNF induce stable growth arrest of Tag-driven β-cancer cells in vitro.
Figure 2: STAT1- and TNFR1-dependent stabilization of the p16INK4a–Rb senescence pathway in β-cancer cells by the combined action of IFN-γ and TNF in vitro.
Figure 3: TNFR1-dependent induction of growth arrest and senescence in β-cancer cells by TH1 immunity in vivo.
Figure 4: T H 1 immunity induces TNFR1-dependent, permanent growth arrest of β-cancer cells that remains stable for ≥10 weeks, even after transfer into immune-deficient NOD–SCID  Il2rg −/− mice.

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Acknowledgements

The authors thank A. Knuth, H. G. Rammensee, K. Ghoreschi, J. Brück, G. Riethmüller, G. Stingl, T. Biedermann and A. Yazdi for discussions, T. Haug for technical support in the chromium release assay, R. Dummer for melanoma samples, W. Kempf for technical support in the cell cycle analysis and S. Lowe for the p16–p19 shRNA concept. The technical assistance of S. Weidemann and M. Dierstein is gratefully acknowledged. This work is part of the doctoral thesis of E.B., S.A., M.H., K.B., J.Berdel and C.G., and was supported by the Sander Stiftung (2005.043.2 and 2005.043.3), the Deutsche Krebshilfe (No. 109037), the IZKF-Promotionskolleg ‘Molekulare Medizin’ 2010 (1886-0-0), 2011 (PK 2011-3) and 2012 (PK 2012-1), the Deutsche Forschungsgemeinschaft (SFB 685, SFB 773 and Wi 1279/3-1) and in part by the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DzD e.V.).

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Author notes

  1. Heidi Braumüller and Thomas Wieder: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Dermatology, Eberhard Karls University, Liebermeister Strasse 25, 72076 Tübingen, Germany,

    Heidi Braumüller, Thomas Wieder, Ellen Brenner, Sonja Aßmann, Matthias Hahn, Manfred Kneilling, Christoph Griessinger, Kilian Braungart, Tarun Mehra, Birgit Fehrenbacher, Julia Berdel, Heike Niessner, Friedegund Meier, Jürgen Bauer, Martin Schaller & Martin Röcken

  2. Department of General Pediatrics, Oncology/Hematology, Eberhard Karls University, Hoppe-Seyler-Strasse 1, 72076 Tübingen, Germany,

    Mohammed Alkhaled, Karin Schilbach & Rupert Handgretinger

  3. Interfaculty Institute for Biochemistry, Eberhard Karls University, Hoppe-Seyler-Strasse 4, 72076 Tübingen, Germany ,

    Frank Essmann & Klaus Schulze-Osthoff

  4. Department for Preclinical Imaging and Radiopharmacy, Laboratory for Preclinical Imaging and Imaging Technology of the Werner Siemens-Foundation, Eberhard Karls University, Röntgenweg 13, 72076 Tübingen, Germany,

    Christoph Griessinger

  5. Department of Internal Medicine IV, Endocrinology, Diabetology and Clinical Chemistry, Eberhard Karls University, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany,

    Felicia Ranta, Susanne Ullrich & Hans-Ulrich Häring

  6. Institut für Molekulare Immunologie, Helmholtz-Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Marchionini Strasse 25, 81377 München, Germany ,

    Ralph Mocikat

  7. Clinic of Oncology, University Hospital Zurich, Raemistrasse 100, 8091 Zürich, Switzerland ,

    Maries van den Broek

  8. Comprehensive Cancer Center Tübingen, German Cancer Consortium (DKTK), Herrenberger Strasse 23, D-72070 Tübingen, Germany ,

    Rupert Handgretinger, Falko Fend, Klaus Schulze-Osthoff & Martin Röcken

  9. Department of Pathology, Eberhard Karls University, Liebermeister Strasse 8, 72076 Tübingen, Germany,

    Leticia Quintanilla-Martinez & Falko Fend

  10. Division of Molecular Oncology of Solid Tumors, Department of Internal Medicine I, Eberhard Karls University, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany,

    Marina Pesic & Lars Zender

Authors
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Contributions

M.R. originally developed the concept, further elaborated on it, and designed the experiments together with H.B., T.W., R.M. and K.S.-O. H.B., T.W., S.A., M.K., C.G., F.E., M.H., K.B., T.M. and E.B. performed experiments and analysed the data. B.F. and M.S. established and carried out fluorescence microscopy. L.Q.-M. and F.F. performed light microscopy and advised on cell biology. M.A., K.S. and R.H. supervised and performed the β-cancer-cell-transfer experiments. L.Z. and M.P. generated shp16–p19 MSCV vectors and supervised the knockdown experiments. H.N. and F.M. isolated primary melanoma cells, J.Berdel and J.Bauer collected human melanoma specimen and performed immunohistochemical analysis. F.R., S.U. and H.-U.H. isolated β-cancer cells and advised on β-cell physiology. H.B., T.W., M.v.d.B., K.S.-O. and M.R. interpreted the data and wrote the paper.

Corresponding author

Correspondence to Martin Röcken.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This fie contains Supplementary Figures 1-16, Supplementary Tables 1-3, a chart showing the clinical and pathological characterization of patients, and a chart showing the sequences for RNA constructs. (PDF 3208 kb)

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Braumüller, H., Wieder, T., Brenner, E. et al. T-helper-1-cell cytokines drive cancer into senescence. Nature 494, 361–365 (2013). https://doi.org/10.1038/nature11824

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