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Human Tumor-Derived Exosomes Selectively Impair Lymphocyte Responses to Interleukin-2

¹ Department of Oncology and Palliative Medicine, School of Medicine, Cardiff University, Velindre Cancer Centre and ² Cancer Services Division, Velindre NHS Trust, Whitchurch, Cardiff, United Kingdom

Requests for reprints: Aled Clayton, Oncology and Palliative Medicine, School of Medicine, Cardiff University, Velindre Cancer Centre, Whitchurch, Cardiff CF14 2TL, United Kingdom. Phone: 44-29-2019-6148; Fax: 11-44-29-529625; E-mail: aled.clayton{at}velindre-tr.wales.nhs.uk.

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 ß₁ (TGFß₁), which contributed to the antiproliferative effects, shown by using neutralizing TGFß₁-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. [Cancer Res 2007;67(15):7458–66]

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