Cancer-associated fibroblasts serve as decoys to suppress NK cell anti-cancer cytotoxicity in breast cancer

Cancer-associated fibroblasts (CAFs) are abundant components of the breast tumor microenvironment and major contributors to immune-modulation. CAFs regulate the activity of many immune cells including T-cells, macrophages and dendritic cells, however little is known about their interaction with natural killer (NK) cells, which constitute an important arm of anti-tumor immunity. Using mouse models of breast cancer and ex-vivo co-cultures, we find that CAFs inhibit NK cell cytotoxicity towards cancer cells. We unravel the mechanism by which suppression occurs, through ligand-receptor engagement between NK cells and CAFs, leading to CAF cytolysis and downregulation of activating receptor expression on NK cells, promoting cancer cell escape from NK cell surveillance. In triple negative breast cancer patients, we find enrichment of NK cells in CAF-rich regions, and upregulation of NK binding ligands on CAFs which correlates with poor disease outcome. These results reveal a CAF-mediated immunosuppressive decoy mechanism with implications for treatment of carcinomas.