Tumor cell-derived extracellular vesicles foster the immunosuppressive landscape of pancreatic cancer.

Pancreatic cancer remains a devastating disease with limited therapeutic options. Accumulating evidence shows that cancer-associated fibroblasts (CAFs) and tumor-associated macrophages, the predominant cells in the pancreatic cancer (PDAC) tumor microenvironment, hinder antitumor immunity. However, the role of extracellular vesicles (EVs) in such a process is poorly understood. In this study, using human bone marrow-derived monocytes and PDAC tumor cells, we showed that tumor cell-derived EVs (TC-EVs) induced monocyte differentiation toward M2-like, immunosuppressive, CD200R+PD-L1+HLA-DRlo macrophages that express ALOX15B, that we identify as an independent PDAC poor-prognosis biomarker using a human PDAC metacohort. We also demonstrated that TC-EVs reprogrammed human primary PDAC CAFs, causing a fibronectin network reorganization associated with changes in extracellular matrix (ECM) composition, including alterations of WNT pathway elements such as secreted frizzled related protein-1 (SFRP1) enrichment. We also revealed that monocytes cultured on SFRP1-enriched ECM differentiated into M2-like, immunosuppressive macrophages. Last, we demonstrated that both directly and indirectly TC-EV- or SFRP1-enriched ECM-driven differentiated macrophages hindered T cell activation and subsequent antitumor activity. Our findings highlight potentially novel dual mechanisms of TC-EV-mediated crosstalk, involving ALOX15B+ macrophages and SFRP1+ CAFs, that simultaneously contribute to foster the immunosuppressive ecosystem of PDAC.