Colorectal cancer-derived extracellular vesicles containing HSP70 enhance macrophage phagocytosis by up-regulating MARCO expression

• Published in: Experimental cell research 2023-05, Vol.426 (2), p.113565-113565, Article 113565
• Main Authors: Sun, Yu, Xiao, Wenjun, Yu, Yang, Jiang, Yuchen, Xiao, Zhijie, Huang, Defa, Zhong, Tianyu, Li, Jiang, Xiang, Xi, He, Yulong, Li, Zhigang
• Format: Article
• Language: English
• Subjects: Colorectal cancer; Colorectal Neoplasms - metabolism; Extracellular vesicles; Extracellular Vesicles - metabolism; HSP70; HSP70 Heat-Shock Proteins - genetics; HSP70 Heat-Shock Proteins - metabolism; Humans; Macrophage; Macrophages - metabolism; MARCO; Phagocytosis; Proteomics; Tumor Microenvironment
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2023.113565

In recent years, we have realized that extracellular vesicles (EVs) play a critical role in regulating the intercellular communication between tumor and immune cells in the tumor microenvironment (TME). Tumor-derived extracellular vesicles (TDEVs) profoundly affect the functional changes of tumor-associated macrophages (TAMs) and promote their M2 polarization. Meanwhile, macrophages have a strong phagocytic ability in phagocytosing apoptotic cells. Especially in the course of chemotherapy or radiotherapy, TAMs can phagocytose and remove apoptotic tumor cells, showing anti-inflammatory and pro-tumor effects. However, the underlying mechanisms by which TDEVs regulate macrophage phagocytosis of apoptotic tumor cells have not been fully elucidated. In this study, we focused on the effect of colorectal cancer-derived extracellular vesicles (CRC-EVs) on macrophages. We demonstrated that CRC-EVs enhanced macrophage phagocytosis of apoptotic CRC cells. We then determined that heat shock protein 70 (HSP70) carried in CRC-EVs was responsible for this effect by using mass spectrometry-based proteomic analysis and the CRISPR-Cas9 system. Through transcriptome sequencing of macrophages, we found that the enhanced phagocytosis of macrophages was mainly due to the up-regulation of the macrophage receptor with collagenous structure (MARCO). In addition, we confirmed that the up-regulation of MARCO was mediated by the AKT-STAT3 signaling pathway. Taken together, this study revealed a novel EVs-mediated macrophage phagocytosis mechanism involved in the clearance of apoptotic tumor cells in the TME. Targeting TDEVs may have potential therapeutic applications in tumor treatment. Graphical Abstract: Schematic model of CRC-EV cargo protein HSP70 enhancing macrophage phagocytosis through activation of AKT-STAT3-MARCO signaling. CRC-EVs deliver HSP70 protein to macrophages and induce AKT phosphorylation, which further promotes STAT3 phosphorylation and translocation into the nucleus. Phosphorylated STAT3 promotes MARCO transcription, translation, and translocation to the surface of macrophages, further enhancing macrophage phagocytosis of apoptotic tumor cells. This clearance of apoptotic tumor cells contributes to CRC progression. [Display omitted] •Colorectal cancer-derived extracellular vesicles (CRC-EVs) promoted macrophage phagocytosis of apoptotic CRC cells.•CRC-EVs up-regulated MARCO expression to enhance macrophage phagocytic activity.•CRC-EVs carried HSP70 to up-regulate