Cancer-secreted exosomal miR-1468-5p promotes tumor immune escape via the immunosuppressive reprogramming of lymphatic vessels.
B7-H1 Antigen
/ genetics
Cellular Reprogramming
/ immunology
Endothelial Cells
/ immunology
Exosomes
/ genetics
Female
Gene Expression Regulation, Neoplastic
/ genetics
Homeodomain Proteins
/ genetics
Humans
Immunity
/ genetics
Immunosuppression Therapy
/ methods
Janus Kinase 2
/ genetics
Lymphangiogenesis
/ genetics
Lymphatic Vessels
/ immunology
MicroRNAs
/ genetics
Promoter Regions, Genetic
/ genetics
STAT3 Transcription Factor
/ genetics
Suppressor of Cytokine Signaling 1 Protein
/ genetics
T-Lymphocytes
/ immunology
Tumor Escape
/ genetics
Tumor Microenvironment
/ immunology
Uterine Cervical Neoplasms
/ genetics
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
07 04 2021
07 04 2021
Historique:
received:
17
08
2020
revised:
11
12
2020
accepted:
23
12
2020
pubmed:
4
1
2021
medline:
20
11
2021
entrez:
3
1
2021
Statut:
ppublish
Résumé
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 microRNAs (miRNAs) have recently been implicated in intercellular crosstalk within the TME. Here, we report a mechanistic model via which cervical cancer-secreted, exosome-encapsulated microRNA (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 homeobox containing 1 (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.
Identifiants
pubmed: 33388421
pii: S1525-0016(20)30727-9
doi: 10.1016/j.ymthe.2020.12.034
pmc: PMC8058488
pii:
doi:
Substances chimiques
B7-H1 Antigen
0
HMBOX1 protein, human
0
Homeodomain Proteins
0
MicroRNAs
0
STAT3 Transcription Factor
0
STAT3 protein, human
0
Suppressor of Cytokine Signaling 1 Protein
0
JAK2 protein, human
EC 2.7.10.2
Janus Kinase 2
EC 2.7.10.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1512-1528Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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