Tumor-derived microvesicles induce, expand and up-regulate biological activities of human regulatory T cells (Treg)

PLoS One. 2010 Jul 22;5(7):e11469. doi: 10.1371/journal.pone.0011469.


Background: Tumor-derived microvesicles (TMV) or exosomes are present in body fluids of patients with cancer and might be involved in tumor progression. The frequency and suppressor functions of peripheral blood CD4(+)CD25(high)FOXP3(+) Treg are higher in patients with cancer than normal controls. The hypothesis is tested that TMV contribute to induction/expansion/and activation of human Treg.

Methodology/principal findings: TMV isolated from supernatants of tumor cells but not normal cells induced the generation and enhanced expansion of human Treg. TMV also mediated conversion of CD4(+)CD25(neg) T cells into CD4(+)CD25(high)FOXP3(+) Treg. Upon co-incubation with TMV, Treg showed an increased FasL, IL-10, TGF-beta1, CTLA-4, granzyme B and perforin expression (p<0.05) and mediated stronger suppression of responder cell (RC) proliferation (p<0.01). Purified Treg were resistant to TMV-mediated apoptosis relative to other T cells. TMV also increased phospho-SMAD2/3 and phospho-STAT3 expression in Treg. Neutralizing Abs specific for TGF-beta1 and/or IL-10 significantly inhibited TMV ability to expand Treg.

Conclusions/significance: This study suggests that TMV have immunoregulatory properties. They induce Treg, promote Treg expansion, up-regulate Treg suppressor function and enhance Treg resistance to apoptosis. Interactions of TMV with Treg represent a newly-defined mechanism that might be involved in regulating peripheral tolerance by tumors and in supporting immune evasion of human cancers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / physiology
  • Blotting, Western
  • CD3 Complex / metabolism
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Cytoplasmic Vesicles / metabolism*
  • Flow Cytometry
  • Humans
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • T-Lymphocytes, Regulatory / metabolism*
  • Tumor Cells, Cultured


  • CD3 Complex
  • Interleukin-2 Receptor alpha Subunit