Journal
ADVANCED SCIENCE
Volume 9, Issue 9, Pages -Publisher
WILEY
DOI: 10.1002/advs.202102620
Keywords
colorectal cancer; macrophage; MicroRNA; PD-L1; small extracellular vesicles
Categories
Funding
- National Natural Science Foundation of China [81672328, 81772636, 81972220]
- Social Development Project of Jiangsu Province [BE2019632]
- Medical Key Professionals Program of Jiangsu Province [AF052141]
- Six Talent Peaks Projects of Jiangsu Province [WSW-196, WSW-155]
- High Level Health Talent Project of Jiangsu Province [LGY2019017, LGY2018012]
- Wuxi Taihu Lake Talent Plan
- Top Talent Support Program for young and middle-aged people of Wuxi Health Committee [BJ2020058]
- Wuxi Medical Innovation Team [CXTP003]
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This study reveals that colorectal cancer cells can induce macrophage polarization and PD-L1 expression through the release of small extracellular vesicles (sEVs), leading to suppressed CD8(+) T cell activity and increased tumor growth. The miR-21-5p and miR-200a derived from sEVs play key regulatory roles in this process. Inhibiting the secretion of specific sEV-miRNAs from CRC and targeting PD-L1 in TAMs may serve as novel methods for CRC treatment.
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-L1(+)CD206(+) 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-L1(+)CD206(+) 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.
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