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Cancer-secreted exosomal miR-1468-5p promotes tumor immune escape via the immunosuppressive reprogramming of lymphatic vessels

Lookup NU author(s): Dr Lei HuangORCiD

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).

Abstract

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.

Publication metadata

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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