Pancreatic cancer cells elevated MARCO expression on tumor-associated macrophages and promote the development of pancreatic ductal adenocarcinoma via inhibiting adaptive immune response

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide. Macrophage receptor with collagenous structure (MARCO) is a scavenger receptor class-A protein expressed on the cell surface of macrophages. However, the role of MARCO-expressing macrophages in the progression of PDAC remains poorly understood. Our study revealed that MARCO-expressing macrophages significantly increased in PDAC patients with lower infiltration of CD8⁺ T cells and NK cells. Studies conducted in vitro with co-cultures of several PDAC cell lines and macrophages revealed that these cell lines markedly elevate MARCO expression in macrophages, leading to pro-tumor polarization in both mice and human. Cell-cell contact analysis indicated that VEGF specifically acts on MARCO⁺ macrophages and VEGF stimulates the expression of MARCO in vitro. Notably, genetic deletion of Marco significantly inhibited the growth of PDAC in mice, at least in part due to the promotion of NK and T cells infiltration. Finally, we confirmed that MARCO⁺macrophages were enriched in several other cancer types, which may be correlated with the progression of these cancers. In conclusion, our findings identified a new potential target for targeting macrophages in the treatment of PDAC and demonstrated that targeting macrophages MARCO may improve the immunosuppressive microenvironment through activation of NK, and T cells functions, thereby treating PDAC.