Cancer‐associated fibroblasts promote M2 polarization of macrophages in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is characterized by remarkable desmoplasia with infiltration of distinct cellular components. Cancer‐associated fibroblasts (CAFs) has been shown to be among the most prominent cells and played a significant role in shaping the tumor microenvironment by interacting with other type of cells. Here, we aimed to investigate the effect of CAFs in modulating phenotype of tumor‐associated macrophages (TAM). Under treatment of CAFs conditioned medium (CM) or direct co‐culture with CAFs, monocytes exhibited enhanced expression of CD206 and CD163 compared with control group (P < 0.01). The induction of M2 polarization was mediated by increased reactive oxygen species (ROS) production in monocytes as ROS elimination abolished the effect of CAFs (P < 0.05). The supernatant analysis showed that pancreatic CAFs produced increased macrophage colony‐stimulating factor (M‐CSF). Upon treatment of M‐CSF neutralizing antibody, the ROS generation and M2 polarization of CAFs CM‐stimulated monocytes were significantly inhibited (P < 0.05). In addition, the CAFs‐induced M2 macrophages significantly enhanced pancreatic tumor cell growth, migration, and invasion. Collectively, our data revealed that pancreatic CAFs were able to induce a tumor‐promoting TAM phenotype partly through secreted M‐CSF and enhanced ROS production in monocytes, indicating possible treatment strategies by targeting stromal cell interaction within PDAC microenvironment.