Browse by author
Lookup NU author(s): Dr Lei HuangORCiD, Emeritus Professor Andrew MellorORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Clinical response to immunotherapy is closely associated with the immunosuppressive tumour microenvironment (TME), and influenced by the dynamic interaction between tumour cells and lymphatic endothelial cells (LECs). Here, we show that high levels of miR-142-5p positively correlate with indoleamine 2,3-dioxygenase (IDO) expression in tumour-associated lymphatic vessels in advanced cervical squamous cell carcinoma (CSCC). The miR-142-5p is transferred by CSCC-secreted exosomes into LECs to exhaust CD8+ T cells via the up-regulation of lymphatic IDO expression, which was abrogated by an IDO inhibitor. Mechanistically, miR-142-5p directly down-regulates lymphatic AT-rich interactive domain-containing protein 2 (ARID2) expression, inhibits DNA methyltransferase 1 (DNMT1) recruitment to interferon (IFN)-γ promoter, and enhances IFN-γ transcription by suppressing promoter methylation, thereby leading to elevated IDO activity. Furthermore, increased serum exosomal miR-142-5p levels and the consequent IDO activity positively correlate with CSCC progression. In conclusion, exosomes secreted by CSCC cells deliver miR-142-5p to LECs and induce IDO expression via ARID2–DNMT1–IFN-γ signalling to suppress and exhaust CD8+ T cells. Our study suggests that LECs act as an integral component of the immune checkpoint(s) in the TME and may serve as a potential new target for CSCC diagnosis and treatment.
Author(s): Zhou C, Zhang Y, Yan R, Huang L, Mellor AL, Yang Y, Chen X, Wei W, Wu X, Yu L, Liang L, Zhang D, Wu S, Wang W
Publication type: Article
Publication status: Published
Journal: Cell Death & Differentiation
Year: 2021
Volume: 28
Pages: 715-729
Print publication date: 01/02/2021
Online publication date: 14/09/2020
Acceptance date: 02/09/2019
Date deposited: 21/10/2020
ISSN (print): 1350-9047
ISSN (electronic): 1476-5403
Publisher: Nature Publishing Group
URL: https://doi.org/10.1038/s41418-020-00618-6
DOI: 10.1038/s41418-020-00618-6
PubMed id: 32929219
Altmetrics provided by Altmetric
