Fibroblast activation protein regulates natural killer cell migration, extravasation and tumor infiltration

Abstract

Natural killer (NK) cells play critical roles in physiologic and pathologic conditions such as pregnancy, infection, autoimmune disease and cancer. In cancer, numerous strategies have been designed to exploit the cytolytic properties of NK cells, with variable success. A major hurdle to NK-cell focused therapies is NK cell recruitment to and infiltration into tumors. While the chemotaxis pathways regulating NK recruitment to different tissues are well delineated, the mechanisms human NK cells employ to physically migrate are ill-defined. We show for the first time that human NK cells express fibroblast activation protein (FAP), a cell surface protease previously thought to be primarily expressed by activated fibroblasts. FAP degrades the extracellular matrix to facilitate cell migration and tissue remodeling. We used novel in vivo zebrafish and in vitro 3D culture models to demonstrate that FAP regulates NK cell migration, extravasation, and infiltration into tumors, ultimately affecting tumor cell lysis. These findings demonstrate the necessity of proteolytic migration in NK cell function, suggest novel mechanisms of action of FAP targeting drugs, and provide an entirely new way to regulate NK cell activity.

The integration of Tgfβ and Egfr signaling programs confers the ability to lead heterogeneous collective invasion

“…3D models allow us to visualize and study single as well as collective cell invasion, making them an ideal choice for our study. 3D organotypic models can also mimic physiologically relevant interactions between tumor and immune cells, allowing researchers to study immune cell induced tumor cell toxicity as well [137,138].…”