Wang Xiaolong, Chen Liang, Zhang Wenwei, Sun Wei, Huang Jianpeng
Department of Gastrointestinal Surgery, Huadu District People's Hospital of Guangzhou, Guangzhou, China.
The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.
Cancer Biother Radiopharm. 2025 Apr;40(3):185-195. doi: 10.1089/cbr.2024.0032. Epub 2024 Sep 12.
Exosomal programmed death ligand 1 (PD-L1), an exosomal membrane protein found in many tumor types, is consider to aid in regulation of the immune microenvironment. However, the functions and the mechanisms underlying the exosome-mediated regulation of the immune microenvironment in colorectal cancer (CRC) remain unknown. Western blotting was used to investigate the levels of exosomal PD-L1 in the peripheral blood of patients with CRC and healthy controls. A CRC mouse model was constructed by administering 10 mg/kg azoxymethane (AOM) and dextrane sodium sulfate (DSS) intraperitoneally. The mice were then administered the control or CRC-derived exosomes to examine the regulatory effect of the exosomes on macrophage infiltration and CRC development. studies, using a coculture system, and flow cytometry analysis were conducted to examine the relationship between the regulatory effect of CRC-derived exosomes on CD4 T cells and tumor-associated macrophages. RNA-seq and reverse transcription-quantitative polymerase chain reaction assays were used to investigate the mechanisms underlying the regulatory effect of the CRC-derived exosomes on macrophage proliferation and the regulation of the immune microenvironment during CRC development. In patients with CRC, higher levels of exosomal PD-L1 were associated with a more severe form of disease. The treatment of mice with AOM/DSS-induced CRC with CRC-derived exosomes resulted in high levels of macrophage proliferation, increased PD-L1 levels in macrophages, and accelerated CRC progression. Importantly, analysis of an coculture system and flow cytometry analysis showed that the CRC-derived exosomes transported PD-L1 into macrophages and impaired CD4 T cell function. Preliminary data suggest that the NF-κb signaling pathway regulates the function of CRC-derived exosomal PD-L1-dependent macrophages. CRC-derived exosomes induce the proliferation of macrophages and increase their PD-L1 levels. They also impair CD4 T cell function and promote CRC progression. Our findings reveal a novel exosomal PD-L1-mediated crosstalk between the CRC cells and immune cells in the CRC microenvironment.
外泌体程序性死亡配体1（PD-L1）是一种存在于多种肿瘤类型中的外泌体膜蛋白，被认为有助于调节免疫微环境。然而，外泌体介导的结直肠癌（CRC）免疫微环境调节的功能和机制仍不清楚。采用蛋白质免疫印迹法检测CRC患者和健康对照者外周血中外泌体PD-L1的水平。通过腹腔注射10mg/kg氧化偶氮甲烷（AOM）和葡聚糖硫酸钠（DSS）构建CRC小鼠模型。然后给小鼠注射对照或CRC来源的外泌体，以检测外泌体对巨噬细胞浸润和CRC发展的调节作用。利用共培养系统和流式细胞术分析，研究CRC来源的外泌体对CD4 T细胞和肿瘤相关巨噬细胞的调节作用之间的关系。采用RNA测序和逆转录定量聚合酶链反应分析，探讨CRC来源的外泌体对巨噬细胞增殖的调节作用及CRC发生发展过程中免疫微环境调节的机制。在CRC患者中，外泌体PD-L1水平越高，疾病形式越严重。用CRC来源的外泌体治疗AOM/DSS诱导的CRC小鼠，导致巨噬细胞增殖水平升高、巨噬细胞中PD-L1水平增加以及CRC进展加速。重要的是，共培养系统分析和流式细胞术分析表明，CRC来源的外泌体将PD-L1转运到巨噬细胞中并损害CD4 T细胞功能。初步数据表明，NF-κB信号通路调节CRC来源的外泌体依赖性巨噬细胞的功能。CRC来源的外泌体诱导巨噬细胞增殖并增加其PD-L1水平。它们还损害CD4 T细胞功能并促进CRC进展。我们的研究结果揭示了CRC微环境中一种新的外泌体PD-L1介导的CRC细胞与免疫细胞之间的串扰。
