βig-h3-structured collagen alters macrophage phenotype and function in pancreatic cancer

Macrophages play an important role in immune and matrix regulation during pancreatic adenocarcinoma (PDAC). Collagen deposition massively contributes to the physical and functional changes of the tissue during pathogenesis. We investigated the impact of thick collagen fibers on the phenotype and function of macrophages. We recently demonstrated that the extracellular protein βig-h3/TGFβi (Transforming growth factor-β-induced protein) plays an important role in modulating the stiffness of the pancreatic stroma. By using atomic force microscopy, we show that βig-h3 binds to type I collagen and establishes thicker fibers. Macrophages cultured on βig-h3-structured collagen layers display a different morphology and a pro-tumoral M2 phenotype and function compared to those cultured on non-structured collagen layers. In vivo injection of those instructed CD206⁺CD163⁺ macrophages was able to suppress T cell responses. These results reveal for the first time that the collagen structure impacts the phenotype and function of macrophages by potentiating their immunosuppressive features.