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.
authors.affiliation: Laboratory of Molecular Biology of the Cell, CNRS UMR5239, IFR128, Ecole Normale Supérieure de Lyon, Lyon 69364, France. biroccio@ifo.it
authors.forename: Annamaria
authors.initials: A
authors.lastname: Biroccio
authors.forename: Julien
authors.initials: J
authors.lastname: Cherfils-Vicini
authors.forename: Adeline
authors.initials: A
authors.lastname: Augereau
authors.forename: Sébastien
authors.initials: S
authors.lastname: Pinte
authors.forename: Serge
authors.initials: S
authors.lastname: Bauwens
authors.forename: Jing
authors.initials: J
authors.lastname: Ye
authors.forename: Thomas
authors.initials: T
authors.lastname: Simonet
authors.forename: Béatrice
authors.initials: B
authors.lastname: Horard
authors.forename: Karine
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authors.lastname: Jamet
authors.forename: Ludovic
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authors.lastname: Cervera
authors.forename: Aaron
authors.initials: A
authors.lastname: Mendez-Bermudez
authors.forename: Delphine
authors.initials: D
authors.lastname: Poncet
authors.forename: Renée
authors.initials: R
authors.lastname: Grataroli
authors.forename: Claire T'kint
authors.initials: CT
authors.lastname: de Rodenbeeke
authors.forename: Erica
authors.initials: E
authors.lastname: Salvati
authors.forename: Angela
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authors.lastname: Rizzo
authors.forename: Pasquale
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authors.lastname: Zizza
authors.forename: Michelle
authors.initials: M
authors.lastname: Ricoul
authors.forename: Céline
authors.initials: C
authors.lastname: Cognet
authors.forename: Thomas
authors.initials: T
authors.lastname: Kuilman
authors.forename: Helene
authors.initials: H
authors.lastname: Duret
authors.forename: Florian
authors.initials: F
authors.lastname: Lépinasse
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Marvel
authors.forename: Els
authors.initials: E
authors.lastname: Verhoeyen
authors.forename: François-Loïc
authors.initials: FL
authors.lastname: Cosset
authors.forename: Daniel
authors.initials: D
authors.lastname: Peeper
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Arturo
authors.initials: A
authors.lastname: Londoño-Vallejo
authors.forename: Laure
authors.initials: L
authors.lastname: Sabatier
authors.forename: Vincent
authors.initials: V
authors.lastname: Picco
authors.forename: Gilles
authors.initials: G
authors.lastname: Pages
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.forename: Antonella
authors.initials: A
authors.lastname: Stoppacciaro
authors.forename: Carlo
authors.initials: C
authors.lastname: Leonetti
authors.forename: Eric
authors.initials: E
authors.lastname: Vivier
authors.forename: Eric
authors.initials: E
authors.lastname: Gilson
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D002448:Cell Adhesion; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D017931:DNA Primers / Q000737:chemistry; D000070819:Discoidin Domain Receptor 1; D005260:Female; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D008819:Mice, Nude; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D035341:Telomeric Repeat Binding Protein 2; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases; D015238:Sulfotransferases; C021350:heparitin sulfotransferase