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

Annamaria Biroccio; Julien Cherfils-Vicini; Adeline Augereau; Sébastien Pinte; Serge Bauwens; Jing Ye; Thomas Simonet; Béatrice Horard; Karine Jamet; Ludovic Cervera; Aaron Mendez-Bermudez; Delphine Poncet; Renée Grataroli; Claire T.Kint De Rodenbeeke; Erica Salvati; Angela Rizzo; Pasquale Zizza; Michelle Ricoul; Céline Cognet; Thomas Kuilman; Helene Duret; Florian Lépinasse; Jacqueline Marvel; Els Verhoeyen; François Loïc Cosset; Daniel Peeper; Mark J. Smyth; Arturo Londoño-Vallejo; Laure Sabatier; Vincent Picco; Gilles Pages; Jean Yves Scoazec; Antonella Stoppacciaro; Carlo Leonetti; Eric Vivier; Eric Gilson

doi:10.1038/ncb2774

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

Annamaria Biroccio, Julien Cherfils-Vicini, Adeline Augereau, Sébastien Pinte, Serge Bauwens, Jing Ye, Thomas Simonet, Béatrice Horard, Karine Jamet, Ludovic Cervera, Aaron Mendez-Bermudez, Delphine Poncet, Renée Grataroli, Claire T.Kint De Rodenbeeke, Erica Salvati, Angela Rizzo, Pasquale Zizza, Michelle Ricoul, Céline Cognet, Thomas KuilmanHelene Duret, Florian Lépinasse, Jacqueline Marvel, Els Verhoeyen, François Loïc Cosset, Daniel Peeper, Mark J. Smyth, Arturo Londoño-Vallejo, Laure Sabatier, Vincent Picco, Gilles Pages, Jean Yves Scoazec, Antonella Stoppacciaro, Carlo Leonetti, Eric Vivier, Eric Gilson

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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.

Original language	English
Pages (from-to)	818-828
Number of pages	11
Journal	Nature Cell Biology
Volume	15
Issue number	7
DOIs	https://doi.org/10.1038/ncb2774
Publication status	Published - 1 Jul 2013

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10.1038/ncb2774

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Biroccio, A., Cherfils-Vicini, J., Augereau, A., Pinte, S., Bauwens, S., Ye, J., Simonet, T., Horard, B., Jamet, K., Cervera, L., Mendez-Bermudez, A., Poncet, D., Grataroli, R., De Rodenbeeke, C. T. K., Salvati, E., Rizzo, A., Zizza, P., Ricoul, M., Cognet, C., ... Gilson, E. (2013). TRF2 inhibits a cell-extrinsic pathway through which natural killer cells eliminate cancer cells. Nature Cell Biology, 15(7), 818-828. https://doi.org/10.1038/ncb2774

@article{8efaac7359034f258e51af49d58af21e,

title = "TRF2 inhibits a cell-extrinsic pathway through which natural killer cells eliminate cancer cells",

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.",

author = "Annamaria Biroccio and Julien Cherfils-Vicini and Adeline Augereau and S{\'e}bastien Pinte and Serge Bauwens and Jing Ye and Thomas Simonet and B{\'e}atrice Horard and Karine Jamet and Ludovic Cervera and Aaron Mendez-Bermudez and Delphine Poncet and Ren{\'e}e Grataroli and {De Rodenbeeke}, {Claire T.Kint} and Erica Salvati and Angela Rizzo and Pasquale Zizza and Michelle Ricoul and C{\'e}line Cognet and Thomas Kuilman and Helene Duret and Florian L{\'e}pinasse and Jacqueline Marvel and Els Verhoeyen and Cosset, {Fran{\c c}ois Lo{\"i}c} and Daniel Peeper and Smyth, {Mark J.} and Arturo Londo{\~n}o-Vallejo and Laure Sabatier and Vincent Picco and Gilles Pages and Scoazec, {Jean Yves} and Antonella Stoppacciaro and Carlo Leonetti and Eric Vivier and Eric Gilson",

note = "Funding Information: The work done in the laboratory of E.G. was supported by La Ligue Nationale Contre Le Cancer ({\'E}quipe Labellis{\'e}e), 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{\textquoteright}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.",

year = "2013",

month = jul,

day = "1",

doi = "10.1038/ncb2774",

language = "English",

volume = "15",

pages = "818--828",

journal = "Nature Cell Biology",

issn = "1465-7392",

number = "7",

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Biroccio, A, Cherfils-Vicini, J, Augereau, A, Pinte, S, Bauwens, S, Ye, J, Simonet, T, Horard, B, Jamet, K, Cervera, L, Mendez-Bermudez, A, Poncet, D, Grataroli, R, De Rodenbeeke, CTK, Salvati, E, Rizzo, A, Zizza, P, Ricoul, M, Cognet, C, Kuilman, T, Duret, H, Lépinasse, F, Marvel, J, Verhoeyen, E, Cosset, FL, Peeper, D, Smyth, MJ, Londoño-Vallejo, A, Sabatier, L, Picco, V, Pages, G, Scoazec, JY, Stoppacciaro, A, Leonetti, C, Vivier, E & Gilson, E 2013, 'TRF2 inhibits a cell-extrinsic pathway through which natural killer cells eliminate cancer cells', Nature Cell Biology, vol. 15, no. 7, pp. 818-828. https://doi.org/10.1038/ncb2774

TY - JOUR

T1 - TRF2 inhibits a cell-extrinsic pathway through which natural killer cells eliminate cancer cells

AU - Biroccio, Annamaria

AU - Cherfils-Vicini, Julien

AU - Augereau, Adeline

AU - Pinte, Sébastien

AU - Bauwens, Serge

AU - Ye, Jing

AU - Simonet, Thomas

AU - Horard, Béatrice

AU - Jamet, Karine

AU - Cervera, Ludovic

AU - Mendez-Bermudez, Aaron

AU - Poncet, Delphine

AU - Grataroli, Renée

AU - De Rodenbeeke, Claire T.Kint

AU - Salvati, Erica

AU - Rizzo, Angela

AU - Zizza, Pasquale

AU - Ricoul, Michelle

AU - Cognet, Céline

AU - Kuilman, Thomas

AU - Duret, Helene

AU - Lépinasse, Florian

AU - Marvel, Jacqueline

AU - Verhoeyen, Els

AU - Cosset, François Loïc

AU - Peeper, Daniel

AU - Smyth, Mark J.

AU - Londoño-Vallejo, Arturo

AU - Sabatier, Laure

AU - Picco, Vincent

AU - Pages, Gilles

AU - Scoazec, Jean Yves

AU - Stoppacciaro, Antonella

AU - Leonetti, Carlo

AU - Vivier, Eric

AU - Gilson, Eric

N1 - Funding Information: 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.

PY - 2013/7/1

Y1 - 2013/7/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84880332846&partnerID=8YFLogxK

U2 - 10.1038/ncb2774

DO - 10.1038/ncb2774

M3 - Article

C2 - 23792691

AN - SCOPUS:84880332846

SN - 1465-7392

VL - 15

SP - 818

EP - 828

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 7

ER -

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

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