title: Tumor-secreted miR-214 induces regulatory T cells: a major link between immune evasion and tumor growth.
abstract: An increased population of CD4(+)CD25(high)Foxp3(+) 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.
authors.affiliation: 1] Jiangsu 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 [2] Wuxi Oncology Institute, the Affiliated Hospital of Jiang Nan University, Wuxi, Jiangsu 214062, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Jiangsu 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.
authors.forename: Xing
authors.initials: X
authors.lastname: Cai
authors.affiliation: Jiangsu 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.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Jiangsu 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.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Liang
authors.affiliation: Jiangsu 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.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Jiangsu 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.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: State 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.
authors.forename: Zuoyun
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Xiulan
authors.initials: X
authors.lastname: Chen
authors.affiliation: Jiangsu 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.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Allergy and Immunology, The Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Yokoyama
authors.affiliation: Jiangsu 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.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.affiliation: Jiangsu 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.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: Jiangsu 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.
authors.forename: Limin
authors.initials: L
authors.lastname: Li
authors.affiliation: Jiangsu 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.
authors.forename: Dongxia
authors.initials: D
authors.lastname: Hou
authors.affiliation: Jiangsu 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.
authors.forename: Lei
authors.initials: L
authors.lastname: Dong
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Xu
authors.affiliation: Department of Allergy and Immunology, The Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Takachika
authors.initials: T
authors.lastname: Hiroi
authors.affiliation: Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Fuquan
authors.initials: F
authors.lastname: Yang
authors.affiliation: State 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.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Ji
authors.affiliation: Jiangsu 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.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Jiangsu 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.
authors.forename: Ke
authors.initials: K
authors.lastname: Zen
authors.affiliation: Jiangsu 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.
authors.forename: Chen-Yu
authors.initials: CY
authors.lastname: Zhang
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D057809:HEK293 Cells; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology; D014183:Transplantation, Heterologous
chemical_list: C547397:MIRN214 microRNA, human; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D016753:Interleukin-10; D051059:PTEN Phosphohydrolase