Fibroblast activation protein cleavage of collagen enhances class A scavenger receptor‐mediated macrophage adhesion (842.12)

Abstract

The importance of interactions between cancer and stromal cells within the tumor microenvironment to tumor progression is well documented. In contrast, how interactions between different stromal cell types, such as fibroblasts and macrophages, support tumor growth is not understood. Increased infiltration and retention of tumor‐associated macrophages (TAMs) in tumors is indicative of poor prognosis in cancer patients. TAMs secrete a variety a factors that activate stromal fibroblasts. Tumor associated fibroblasts (TAFs) differ from quiescent fibroblasts by upregulating the expression of type 1 collagen, the primary component of the tumor extracellular matrix, and by expressing the post‐prolyl serine protease, fibroblast activation protein (FAP). In this study, we used a quenched fluorescent substrate to show that FAP proteolytically cleaves type 1 collagen, and that the adhesion of primary macrophages to collagen‐1 is substantially increased by FAP‐mediated cleavage. Further, using macrophages isolated from knock‐out mice and specific receptor inhibitory approaches, we show that increased macrophage adhesion to FAP‐modified collagen is mediated by the Class A Scavenger Receptor (SR‐A). These results suggest a novel TAF‐TAM axis in which FAP can promote tumor progression by cleaving collagen and increasing the SR‐A‐dependent retention of TAMs.