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

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Biroccio, Annamaria | Cherfils-Vicini, Julien | Augereau, Adeline | Pinte, Sébastien | Bauwens, Serge | Ye, Jing | Simonet, Thomas | Horard, Béatrice | Jamet, Karine | Cervera, Ludovic | Mendez-Bermudez, Aaron | Poncet, Delphine | Grataroli, Renée | de Rodenbeeke, Claire t'Kint | Salvati, Erica | Rizzo, Angela | Zizza, Pasquale | Ricoul, Michelle | Cognet, Céline | Kuilman, Thomas | Duret, Helene | Lépinasse, Florian | Marvel, Jacqueline | Verhoeyen, Els | Cosset, François-Loïc | Peeper, Daniel | Smyth, Mark | Londoño-Vallejo, Arturo | Sabatier, Laure | Picco, Vincent | Pages, Gilles | Scoazec, Jean-Yves | Stoppacciaro, Antonella | Leonetti, Carlo | Vivier, Eric | Gilson, Eric | de Rodenbeeke, Claire T’kint

Edité par CCSD ; Nature Publishing Group -

International audience. 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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