Colorectal Cancer-Derived Small Extracellular Vesicles Promote Tumor Immune Evasion by Upregulating PD-L1 Expression in Tumor-Associated Macrophages.

Tumor-associated macrophages (TAMs) are one of the most abundant cell types in colorectal cancer (CRC) tumor microenvironment (TME). Recent studies observed complicated "cross-talks" between cancer cells and macrophages in TME. However, the underlying mechanisms are still poorly elucidated. Here, PD-L1 levels are very low in CRC cells but highly abundant in TAMs, and a specific PD-L1CD206 macrophage subpopulation are identified, which is induced by tumor cells and associated with a poor prognosis. Mechanistic investigations reveal that CRC cells can secrete small extracellular vesicles (sEVs) taken up by macrophages that induce M2 like polarization and PD-L1 expression, resulting in increased PD-L1CD206 macrophage abundance and decreased T cell activity in CRC TME. sEV-derived miR-21-5p and miR-200a are identified as key signaling molecules mediating the regulatory effects of CRC on macrophages. Further studies reveal that CRC-derived miR-21-5p and miR-200a synergistically induces macrophage M2 like polarization and PD-L1 expression by regulating the PTEN/AKT and SCOS1/STAT1 pathways, resulting in decreased CD8 T cell activity and increased tumor growth. This study suggests that inhibiting the secretion of specific sEV-miRNAs from CRC and targeting PD-L1 in TAMs may serve as novel methods for CRC treatment as well as a sensitization method for anti-PD-L1 therapy in CRC.