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Methotrexate-loaded tumour-cell-derived microvesicles can relieve biliary obstruction in patients with extrahepatic cholangiocarcinoma

Nature Biomedical Engineering volume 4, pages 743–753 (2020)Cite this article

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Abstract

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.

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Fig. 1: Effective treatment of obstructive CCA with MTX–TMPs.
Fig. 2: MTX–TMP perfusion attracts antitumor neutrophils.
Fig. 3: Direct attraction of neutrophils by UDPG in MTX–TMPs.
Fig. 4: MTX–TMPs induce CCA-cell pyroptosis.
Fig. 5: MTX–TMP perfusion triggers a secondary wave of recruiting neutrophils.
Fig. 6: MTX–TMP perfusion-recruited neutrophils display an antitumour phenotype.

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Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are too large to be publicly shared, but are available for research purposes from the corresponding authors on reasonable request.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (81788101, 81661128007, 81530080, 81773062 and 91942314), the Chinese Academy of Medical Sciences Initiative for Innovative Medicine (CAMS-I2M) (2017-I2M-1-001 and 2016-I2M-1-007).

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Author notes

  1. These authors contributed equally: Yunfeng Gao, Hui Zhang, Nannan Zhou.

Authors and Affiliations

  1. 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

    Yunfeng Gao, Nannan Zhou, Xun Jin, Xiaoyu Liang, Jiadi Lv, Jing Xie, Yuying Liu & Bo Huang

  2. Surgical Oncology, Tianjin Nankai Hospital, Tianjin, China

    Hui Zhang, Jianxiong Wang & Yuan Gao

  3. Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Pingwei Xu, Ke Tang, Jingwei Ma, Huafeng Zhang & Bo Huang

  4. Department of Hepatobiliary Surgery, Tianjin First Center Hospital, Tianjin, China

    Yamin Zhang

  5. Department of Gastro-intestinal Medicine, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

    Fang Yao

  6. Department of Pathology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    Weimin Tong

  7. Clinical Immunology Center, Chinese Academy of Medical Sciences, Beijing, China

    Yuying Liu & Bo Huang

  8. Tianjin ITCWM Clinical Research Centre, Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Tianjin Medical University, Nankai Hospital, Tianjin, China

    Ximo Wang

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Contributions

B.H., Y.L. and X.W. conceived the project. Y.L., Yunfeng Gao, Hui Zhang, N.Z., P.X., J.W., Yuan Gao, X.J., X.L., J.L., Y.Z., K.T., J.M., Huafeng Zhang and J.X. performed the experiments. B.H., Y.L., F.Y., W.T. and X.W. developed methodology. B.H., Y.L., Yunfeng Gao, Hui Zhang and X.W. performed data analysis. B.H. and Y.L. wrote the manuscript.

Corresponding authors

Correspondence to Yuying Liu, Ximo Wang or Bo Huang.

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Competing interests

B.H. is the inventor on patent no. ZL201110241369.8, owned by Hubei Soundny (Sheng-Qi-An) Biotech, which covers the preparation and use of drug-packaging tumour-cell-derived microparticles in cancer therapies. The other authors declare no competing interests.

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Gao, Y., Zhang, H., Zhou, N. et al. Methotrexate-loaded tumour-cell-derived microvesicles can relieve biliary obstruction in patients with extrahepatic cholangiocarcinoma. Nat Biomed Eng 4, 743–753 (2020). https://doi.org/10.1038/s41551-020-0583-0

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