2. Academic Validation
  3. Exosome-derived miR-142-5p remodels lymphatic vessels and induces IDO to promote immune privilege in the tumour microenvironment

Exosome-derived miR-142-5p remodels lymphatic vessels and induces IDO to promote immune privilege in the tumour microenvironment

  • Cell Death Differ. 2021 Feb;28(2):715-729. doi: 10.1038/s41418-020-00618-6.
Chenfei Zhou  # 1,  Yanmei Zhang  # 2,  Ruiming Yan  # 1,  Lei Huang 3,  Andrew L Mellor 3,  Yang Yang 1,  Xiaojing Chen 1,  Wenfei Wei 1,  Xiangguang Wu 1,  Lan Yu 1,  Luojiao Liang 1,  Dan Zhang 4,  Sha Wu 5,  Wei Wang 6
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China.
  • 2 Department of Immunology/Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 3 Institute of Cellular Medicine, Faculty of Medical Sciences, Framlington Place, Newcastle University, Newcastle-Upon-Tyne, NE2 4HH, UK.
  • 4 Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
  • 5 Department of Immunology/Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China. shawu99@outlook.com.
  • 6 Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China. smugowwang@126.com.
  • # Contributed equally.
PMID: 32929219 DOI: 10.1038/s41418-020-00618-6
Abstract

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.

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