Volume 24, No 10, Oct 2014

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 24 Issue 10, October 2014: 1164-1180   |  Open Access

ORIGINAL ARTICLES

Tumor-secreted miR-214 induces regulatory T cells: a major link between immune evasion and tumor growth

Yuan Yin^1,6,*, Xing Cai^1,*, Xi Chen^1,*, Hongwei Liang^1,*, Yujing Zhang¹, Jing Li¹, Zuoyun Wang², Xiulan Chen³, Wen Zhang¹, Seiji Yokoyama⁴, Cheng Wang¹, Liang Li¹, Limin Li¹, Dongxia Hou¹, Lei Dong¹, Tao Xu⁵, Takachika Hiroi⁴, Fuquan Yang³, Hongbin Ji², Junfeng Zhang¹, Ke Zen¹ and Chen-Yu Zhang¹

¹Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology (JERC-MBB), State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
²State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China
³Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
⁴Department of Allergy and Immunology, The Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
5National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
⁶Wuxi Oncology Institute, the Affiliated Hospital of Jiang Nan University, Wuxi, Jiangsu 214062, China Correspondence: Chen-Yu Zhang, E-mail: cyzhang@nju.edu.cn; Ke Zen, E-mail: kzen@nju.edu.cn; Junfeng Zhang,(jfzhang@nju.edu.cn)

An increased population of CD4+CD25highFoxp3+ regulatory T cells (Tregs) in the tumor-associated microenvironment plays an important role in cancer immune evasion. However, the underlying mechanism remains unclear. Here we observed an increased secretion of miR-214 in various types of human cancers and mouse tumor models. Tumor-secreted miR-214 was sufficiently delivered into recipient T cells by microvesicles (MVs). In targeted mouse peripheral CD4+ T cells, tumor-derived miR-214 efficiently downregulated phosphatase and tensin homolog (PTEN) and promoted Treg expansion. The miR-214-induced Tregs secreted higher levels of IL-10 and promoted tumor growth in nude mice. Furthermore, in vivo studies indicated that Treg expansion mediated by cancer cell-secreted miR-214 resulted in enhanced immune suppression and tumor implantation/growth in mice. The MV delivery of anti-miR-214 antisense oligonucleotides (ASOs) into mice implanted with tumors blocked Treg expansion and tumor growth. Our study reveals a novel mechanism through which cancer cell actively manipulates immune response via promoting Treg expansion.

10.1038/cr.2014.121

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