Cancer-Associated Fibroblasts Serve as Decoys to Suppress NK Cell Anticancer Cytotoxicity in Breast Cancer

Abstract Cancer-associated fibroblasts (CAF) 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 NK cells, which constitute an important arm of antitumor immunity. Using mouse models of breast cancer and ex vivo cocultures, we find that CAFs inhibit NK cell cytotoxicity toward cancer cells. We unravel the mechanism by which suppression occurs, which is 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 patients with triple-negative breast cancer, we find enrichment of NK cells in CAF-rich regions and upregulation of NK-binding ligands on CAFs, which correlates with poor disease outcomes. These results reveal a CAF-mediated immunosuppressive decoy mechanism with implications for the treatment of carcinomas. Significance: Little is known about the influence of CAFs on NK cells in the context of carcinomas. Here, we mechanistically unravel a pathway of CAF-mediated suppression of NK cells in breast cancer, opening possible avenues for new biomarkers and strategies for immune-based therapies. See related commentary by Sherman, p. 1096