Human breast tumor cells induce self-tolerance mechanisms to avoid NKG2D-mediated and DNAM-mediated NK-cells recognition
A partir de données portant sur des tumeurs du sein et à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel les cellules de cancer du sein échappent au processus d'immunité anti-tumorale des cellules NK
Breast cancer is the first cause of death for women between the ages of 35 to 65. This is mostly due to inter-tumor heterogeneity and the lack of specific therapies for all subtypes. However, some breast cancers with an unexpected good prognosis are associated with enhanced anti-tumor immunity in situ. We studied whether breast cancer subtypes might have different susceptibility to NK-cells anti-tumor immunity. We collected a large public set of microarray data for primary breast tumors and determined NK-cell-ligands expression. We found that despite heterogeneous levels of inhibitory HLA-members, NKG2D-Ligands and DNAM-ligands are expressed in virtually all breast tumor subtypes. Functional experiments in breast cancer subtypes expressing various levels of NK-cells ligands showed that NK-mediated cytotoxicity is mainly HLA-, NKG2D- and DNAM-dependent. In parallel, we showed that cell lines and primary breast tumor cells secrete soluble inhibitory factors that alter NK-cells functions. Finally, we showed that these mechanisms of escape occur in vivo in the MMTV-Neu model of spontaneous murine breast cancer. Our study demonstrates that breast cancer cells, independently of the subtypes, have developed different mechanisms to escape from NK-cells anti-tumor immunity. These results emphasize the role of NK-cells in breast tumor clearance and underlie the importance to devise future therapy aiming at enhancing NK-cell-mediated recognition in parallel with the prevention of the tumor-editing process.
Cancer Research 2011