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

Annamaria Biroccio (1) , Julien Cherfils-Vicini (2) , Adeline Augereau (3) , Sébastien Pinte (3) , Serge Bauwens (4) , Jing Ye , Thomas Simonet (3) , Béatrice Horard (2) , Karine Jamet (5) , Ludovic Cervera (2) , 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 Smyth , Arturo Londoño-Vallejo , Laure Sabatier , Vincent Picco , Gilles Pages , Jean-Yves Scoazec , Antonella Stoppacciaro , Carlo Leonetti , Eric Vivier , Eric Gilson , Claire T’kint de Rodenbeeke

1 Experimental Chemotherapy Laboratory
2 IRCAN - Institut de Recherche sur le Cancer et le Vieillissement
3 LBMC - Laboratoire de Biologie Moléculaire de la Cellule
4 LBMC UMR 5239 - Laboratoire de biologie et modélisation de la cellule
5 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire

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.

Domaines: Sciences du Vivant [q-bio]

Annamaria Biroccio, Julien Cherfils-Vicini, Adeline Augereau, Sébastien Pinte, Serge Bauwens, et al.. TRF2 inhibits a cell-extrinsic pathway through which natural killer cells eliminate cancer cells. Nature Cell Biology, 2013, 15 (7), pp.818-828. ⟨10.1038/ncb2774⟩. ⟨hal-03510917⟩