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


RESULTS
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
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.
Szajnik
Marta
M
University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America.
Czystowska
Malgorzata
M
Szczepanski
Miroslaw J
MJ
Mandapathil
Magis
M
Whiteside
Theresa L
TL
D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D022162:Cytoplasmic Vesicles / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D017252:CD3 Complex; D053645:Interleukin-2 Receptor alpha Subunit