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Lookup NU author(s): Dr Lei HuangORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
Cancer-associated lymphatic endothelial cells (LECs) are an active barrier to the effector arm of the anti-tumor immune response; however, it remains unclear how LECs become immunosuppressive in the tumor microenvironment (TME). Exosomal miRNAs have recently been implicated in intercellular crosstalk within the TME. Here we report a mechanistic model via which cervical cancer-secreted, exosome-encapsulated miR-1468-5p promotes lymphatic PD-L1 upregulation and lymphangiogenesis to impair T cell immunity. Subsequently, exosomal miR-1468-5p epigenetically activates the JAK2/STAT3 pathway in LECs by directly targeting HMBOX1 in the SOCS1 promoter, activating an immunosuppressive program that allows cancer cells to escape anti-cancer immunity. Furthermore, clinical data reveal that high serum exosomal miR-1468-5p levels correlate with TME immunosuppressive status and poor prognosis in cervical cancer (CCa) patients. Taken together, our results suggest that cancer-secreted exosomal miR-1468-5p instructs LECs to form an integrated immunosuppressive TME component and may be a prognostic biomarker and therapeutic target for CCa.
Author(s): Zhou C, Wei W, Ma J, Yang Y, Liang L, Zhang Y, Wang Z, Chen X, Huang L, Wang W, Wu Sha
Publication type: Article
Publication status: Published
Journal: Molecular Therapy
Year: 2021
Volume: 29
Issue: 4
Pages: 1512-1528
Print publication date: 07/04/2021
Online publication date: 01/01/2021
Acceptance date: 23/12/2020
Date deposited: 18/01/2021
ISSN (print): 1525-0016
ISSN (electronic): 1525-0024
Publisher: Cell Press
URL: https://doi.org/10.1016/j.ymthe.2020.12.034
DOI: 10.1016/j.ymthe.2020.12.034
PubMed id: 33388421
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