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TRF2 inhibits a cell-extrinsic pathway through which natural killer cells eliminate cancer cells

Nature Cell Biology volume 15, pages 818–828 (2013)Cite this article

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Abstract

Dysfunctional telomeres suppress tumour progression by activating cell-intrinsic programs that lead to growth arrest. Increased levels of TRF2, a key factor in telomere protection, are observed in various human malignancies and contribute to oncogenesis. We demonstrate here that a high level of TRF2 in tumour cells decreased their ability to recruit and activate natural killer (NK) cells. Conversely, a reduced dose of TRF2 enabled tumour cells to be more easily eliminated by NK cells. Consistent with these results, a progressive upregulation of TRF2 correlated with decreased NK cell density during the early development of human colon cancer. By screening for TRF2-bound genes, we found that HS3ST4—a gene encoding for the heparan sulphate (glucosamine) 3-O-sulphotransferase 4—was regulated by TRF2 and inhibited the recruitment of NK cells in an epistatic relationship with TRF2. Overall, these results reveal a TRF2-dependent pathway that is tumour-cell extrinsic and regulates NK cell immunity.

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Figure 1: TRF2 dosage modulates the tumorigenicity of mouse and human tumour cells.
Figure 2: Partial TRF2 inhibition does not impair in vitro growth properties of various tumour cell lines.
Figure 3: Partial TRF2 inhibition in various tumour cell lines does not uncap telomeres.
Figure 4: IL-6 is necessary and sufficient to prevent telomere uncapping on TRF2 partial inhibition.
Figure 5: The modulation of tumorigenicity by TRF2 dosage correlates with NK cell recruitment and activation.
Figure 6: The reduced tumorigenicity of TRF2-compromised cells is dependent on NK cells.
Figure 7: TRF2 dosage influences NK cell infiltration in a HS3ST4-dependent manner.
Figure 8: TRF2 expression is negatively correlated with NK cell density during the early stages of colon carcinogenesis.

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Acknowledgements

The work done in the laboratory of E.G. was supported by La Ligue Nationale Contre Le Cancer (Équipe Labellisée), Institut National du Cancer (TELOFUN and TELOCHROM programme), ANR (INNATELO programme) and the European Union (FP7-Telomarker, Health-F2-2007-200950). The E.V. laboratory is supported by ANR (programme INNATELO) and the European Union (ERC advanced grant THINK). We thank L. Zitvogel (Institut Gustave Roussy, France) for providing the XMG1.2 clone, R. Weinberg (Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA) for providing the BJ-HELT cells, C. Delprat (University of Lyon, France) for Luminex analyses, J. Lingner (Ecole Polytechnique Fdrale de Lausanne, Switzerland) for providing the ATR shRNA and ATM shRNA plasmids, and V. Leopold (IRCAN, France) for providing the subcloning vectors. We are also grateful to C. D’Angelo and M. Scarsella for technical support. This work was performed using the microscopy (PICMI), cytometry (CYTOMED) and animal house facilities of IRCAN. The work done by the A.B. group was supported by grants from the Italian Association for Cancer Research (#11567 and #9979). A.B. was supported by the Short-Term Fellowship Programme of the EMBO. M.J.S. was supported by a National Health and Medical Research Council Australia Fellowship. J.C-V. was supported by a postdoctoral fellowship from La Ligue Nationale Contre Le Cancer.

Author information

Author notes

  1. Sébastien Pinte & Delphine Poncet

    Present address: Present addresses: Biology Institute of Lille, CNRS UMR8161, Pasteur Institute of Lille, BP 447, 59021, LILLE cedex, France (S.P.); EA 3738, Laboratoire de Radiobiologie Cellulaire et Moléculaire, Faculté de Médecine Lyon-sud, 69 921 Oullins cedex, Lyon, France (D.P.),

  2. Annamaria Biroccio, Julien Cherfils-Vicini and Adeline Augereau: These authors contributed equally to this work

Authors and Affiliations

  1. Laboratory of Molecular Biology of the Cell, CNRS UMR5239, IFR128, Ecole Normale Supérieure de Lyon, Lyon 69364, France

    Annamaria Biroccio, Adeline Augereau, Sébastien Pinte, Serge Bauwens, Jing Ye, Thomas Simonet, Béatrice Horard, Delphine Poncet, Renée Grataroli, Claire T’kint de Rodenbeeke & Eric Gilson

  2. Regina Elena National Cancer Institute, Rome 00158, Italy

    Annamaria Biroccio, Erica Salvati, Angela Rizzo, Pasquale Zizza & Carlo Leonetti

  3. Institute for Research on Cancer and Aging, Nice (IRCAN), Nice University, CNRS UMR7284/INSERM U1081, Faculty of Medicine, Nice 06107, France

    Julien Cherfils-Vicini, Adeline Augereau, Jing Ye, Karine Jamet, Ludovic Cervera, Aaron Mendez-Bermudez, Vincent Picco, Gilles Pages & Eric Gilson

  4. Shanghai Jiaotong University, Shanghai Ruijin Hospital, Shanghai 200025, China

    Jing Ye

  5. Commissariat à l’Energie Atomique, DSV-Radiobiology and Oncology Unit, BP6 92265 Fontenay-aux-Roses, France

    Michelle Ricoul & Laure Sabatier

  6. Centre d’Immunologie de Marseille-Luminy, Aix-Marseille Université,UM2 INSERM UMR1104, CNRS UMR7280, Marseille 13288, France

    Céline Cognet & Eric Vivier

  7. Hôpital de la Conception, Assistance Publique–Hôpitaux de Marseille, Marseille 13005, France

    Céline Cognet & Eric Vivier

  8. Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands

    Thomas Kuilman & Daniel Peeper

  9. Cancer Immunology Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, 3002 Victoria, Australia

    Helene Duret & Mark J. Smyth

  10. Hospices Civils de Lyon, Hôpital Edouard Herriot, Service d’Anatomie Pathologique, 69437 Lyon cedex 03, France

    Florian Lépinasse & Jean-Yves Scoazec

  11. INSERM, UMR1052, Faculté Laennec, 69372 Lyon cedex 08, France

    Florian Lépinasse & Jean-Yves Scoazec

  12. Université Lyon 1, IFR128, Institut National de la Santé et de la Recherche Médicale, U851, Lyon 69366, France

    Jacqueline Marvel

  13. INSERM U758. ENS de Lyon, 46 Allee d’Italie, 69364 Lyon Cedex 07, France

    Els Verhoeyen & François-Loïc Cosset

  14. Immunology in Cancer and Infection, Queensland Institute of Medical Research, 300 Herston Road, Herston, 4006 Queensland, Australia

    Mark J. Smyth

  15. UMR3244, Institut Curie-UPMC-CNRS 26, rue d’Ulm, 75248 Paris, France

    Arturo Londoño-Vallejo

  16. Experimental Medicine and Pathology Department II Faculty, S. Andrea, Rome 00189, Italy

    Antonella Stoppacciaro

  17. Department of Medical Genetics, Archet 2 Hospital, CHU of Nice, BP 3079, 06202 Nice cedex 3, France

    Eric Gilson

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Contributions

A.B. designed and interpreted most of the experiments and wrote the manuscript; J.C-V. designed, performed and interpreted syngenic mouse experiments, NK cell experiments and HS3ST4 experiments, and wrote the manuscript; A.A. designed, performed and interpreted the IL-6 experiments, contributed to several cell biology experiments and wrote the manuscript; S.P. performed and interpreted cell biology experiments; S.B. performed and interpreted TIF analyses and lentivirus production; J.Y. designed and performed NK cell experiments, and contributed to TIF analyses and lentivirus production; T.S., B.H. and A.M-B. performed and interpreted ChIP experiments; K.J. performed bioinformatic analyses; L.C. performed cytometry analyses; C.T.d.R. and D. Poncet performed gene expression analysis; E.S., A.R., P.Z. and R.G. performed cell biology and mouse experiments; L.S. and M.R. performed and analysed metaphase experiments; C.C. performed and interpreted NK cell experiments; T.K. and D. Peeper provided IL-6 tools and help in analysing the data; H.D. produced IL-12 antibodies; F.L. performed the pathological analyses on colon samples; J.M. provided mouse cell lines; E. Verhoeyen and F-L.C. contributed to lentiviral production; M.J.S. designed experiments, provided 1L-12 antibodies and edited the manuscript; A.L.V. provided cell lines and contributed to telomere analyses; V.P. and G.P. designed, performed and analysed the A375 experiments; J-Y.S. designed and interpreted the colon sample experiments, and wrote the manuscript; A.S. designed, performed and interpreted the pathological experiments with mouse tumours; C.L. designed, performed and interpreted most of the xenograft experiments; E. Vivier designed and interpreted the NK cell experiments, and wrote the manuscript; E.G. designed and coordinated all of the experiments, interpreted the results and wrote the manuscript.

Corresponding authors

Correspondence to Annamaria Biroccio or Eric Gilson.

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The authors declare no competing financial interests.

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Biroccio, A., Cherfils-Vicini, J., Augereau, A. et al. TRF2 inhibits a cell-extrinsic pathway through which natural killer cells eliminate cancer cells. Nat Cell Biol 15, 818–828 (2013). https://doi.org/10.1038/ncb2774

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