Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Surgical Oncology, Tianjin Nankai Hospital, Tianjin, China.
Nat Biomed Eng. 2020 Jul;4(7):743-753. doi: 10.1038/s41551-020-0583-0. Epub 2020 Jul 6.
Most patients with cholangiocarcinoma (CCA) develop extrahepatic malignant biliary obstructions, which require palliative drainage to normalize bilirubin levels and to improve the patients' overall survival. Here, we report that the infusion of methotrexate-containing plasma-membrane microvesicles derived from apoptotic human tumour cells into the bile-duct lumen of patients with extrahepatic CCA mobilized and activated neutrophils and relieved biliary obstruction in 25% of the patients. Neutrophil recruitment by the microvesicles was associated with an increase in uridine diphosphate glucose and complement C5, and led to the degradation of the stromal barrier of CCA. The microvesicles induced pyroptosis of CCA cells through a gasdermin E-dependent pathway, and their intracellular contents released upon CCA-cell death activated patient-derived macrophages into producing proinflammatory cytokines, which attracted a secondary wave of neutrophils to the tumour site. Our findings suggest a possible treatment for the alleviation of obstructive extrahepatic CCA with few adverse effects, and highlight the potential of tumour-cell-derived microvesicles as drug carriers for antitumour therapies.
大多数胆管癌（CCA）患者会出现肝外恶性胆道梗阻，需要姑息性引流来使胆红素水平正常化，并改善患者的总体生存。在这里，我们报告称，将含有甲氨蝶呤的源自凋亡人肿瘤细胞的质膜微囊泡输注到肝外 CCA 患者的胆管腔内，可动员和激活中性粒细胞，并使 25%的患者胆道阻塞得到缓解。微囊泡对中性粒细胞的募集与尿苷二磷酸葡萄糖和补体 C5 的增加有关，并导致 CCA 基质屏障的降解。微囊泡通过依赖于 gasdermin E 的途径诱导 CCA 细胞发生细胞焦亡，并且在 CCA 细胞死亡时释放的细胞内内容物激活了源自患者的巨噬细胞产生促炎细胞因子，从而吸引第二波中性粒细胞到肿瘤部位。我们的研究结果表明，对于缓解梗阻性肝外 CCA 具有很少的副作用的一种可能的治疗方法，并强调了肿瘤细胞衍生的微囊泡作为抗肿瘤治疗药物载体的潜力。
