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

M Szajnik, M Czystowska, MJ Szczepanski… - PloS one, 2010 - journals.plos.org
M Szajnik, M Czystowska, MJ Szczepanski, M Mandapathil, TL Whiteside
PloS one, 2010journals.plos.org
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+ CD25highFOXP3+ 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 …
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+CD25highFOXP3+ 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+CD25neg T cells into CD4+CD25highFOXP3+ Treg. Upon co-incubation with TMV, Treg showed an increased FasL, IL-10, TGF-β1, 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-β1 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.
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