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

Cell Res. 2014 Oct;24(10):1164-80. doi: 10.1038/cr.2014.121. Epub 2014 Sep 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Line, Tumor
  • Cell Proliferation
  • HEK293 Cells
  • Humans
  • Interleukin-10 / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / metabolism*
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Oligonucleotides, Antisense / metabolism
  • PTEN Phosphohydrolase / metabolism
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / immunology
  • Transplantation, Heterologous

Substances

  • MIRN214 microRNA, human
  • MicroRNAs
  • Oligonucleotides, Antisense
  • Interleukin-10
  • PTEN Phosphohydrolase