Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2.
Exosomes are nanometer-sized vesicles, secreted by normal and neoplastic cells. The outcome following interaction between the cellular immune system and cancer-derived exosomes is not well understood. Interleukin-2 (IL-2) is a key factor supporting expansion and differentiation of CTL and natural killer (NK) cells but can also support regulatory T cells and their suppressive functions. Our study examined whether tumor-derived exosomes could modify lymphocyte IL-2 responses. Proliferation of healthy donor peripheral blood lymphocytes in response to IL-2 was inhibited by tumor exosomes. In unfractionated lymphocytes, this effect was seen in all cell subsets. Separating CD4(+) T cells, CD8(+) T cells, and NK cells revealed that CD8(+) T-cell proliferation was not inhibited in the absence of CD4(+) T cells and that NK cell proliferation was only slightly impaired. Other exosome effects included selective impairment of IL-2-mediated CD25 up-regulation, affecting all but the CD3(+)CD8(-) T-cell subset. IL-2-induced Foxp3 expression by CD4(+)CD25(+) cells was not inhibited by tumor exosomes, and the suppressive function of CD4(+)CD25(+) T cells was enhanced by exosomes. In contrast, exosomes directly inhibited NK cell killing function in a T-cell-independent manner. Analysis of tumor exosomes revealed membrane-associated transforming growth factor beta(1) (TGFbeta(1)), which contributed to the antiproliferative effects, shown by using neutralizing TGFbeta(1)-specific antibody. The data show an exosome-mediated mechanism of skewing IL-2 responsiveness in favor of regulatory T cells and away from cytotoxic cells. This coordinated "double hit" to cellular immunity strongly implicates the role of exosomes in tumor immune evasion.
Clayton
Aled
A
Department of Oncology and Palliative Medicine, School of Medicine, Cardiff University, Velindre Cancer Centre, Whitchurch, Cardiff, United Kingdom. aled.clayton@velindre-tr.wales.nhs.uk
Mitchell
J Paul
JP
Court
Jacquelyn
J
Mason
Malcolm D
MD
Tabi
Zsuzsanna
Z
D015153:Blotting, Western; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005089:Exocytosis / Q000276:immunology*; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000494:pharmacology*; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D010997:Pleural Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000378:metabolism
D007376:Interleukin-2; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10