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

Abstract

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 À 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 B 1 (TGFB 1 ), which contributed to the antiproliferative effects, shown by using neutralizing TGFB 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. [Cancer Res 2007;67(15):7458-66]

Cell-Cell Communication Via Extracellular Membrane Vesicles and Its Role in the Immune Response

“…Exosomes originating from immune cells routinely carry a host of immunoregulatory proteins, such as cytokines (e.g., TNF-α, IL-1, IL-18, etc.) (Clayton et al, 2007;Turola et al, 2012). Of interest, a large portion of proteins in exosomes are found polyubiquitinated (Luzio et al, 2009), suggesting that exosomal proteins are subjected to protein degradation by lysosomal enzymes unless they are released to the extracellular space following fusion of the late endosomes to the plasma membrane Exosomes as a carrier of RNAs Besides proteins, exosomes also carry nucleic acids (Chaput and Thery, 2011;Zomer et al, 2010).…”

“…Exosomes from tumor cells can have effects on immune cells, resulting in promotion or suppression of the host immunity to the tumor (Clayton et al, 2007;Filipazzi et al, 2012;Gastpar et al, 2005;Taylor and Gercel-Taylor, 2011). Earlier studies showed that immunization of mice with exosomes prepared from tumor cells reduced the growth of implanted tumor cells.…”

Relevance of circulating tumor cells, extracellular nucleic acids, and exosomes in breast cancer

“…It is thought the contents of exosomes depend on their cell of origin [78]; those derived from immune cells having immunostimulatory and anti-tumor effects in vivo [89], while those derived from tumor cells accelerate tumor growth [78,90] and invasiveness [91,92]. Additionally, the RNA contained within exosomes is amplifiable; suggesting protection from RNase degradation by the exosome membrane [78].…”

Isolation of Exosomes for Subsequent mRNA, MicroRNA, and Protein Profiling

“…Exosomes have also been described as having both immunostimulatory and anti-tumour affects in vivo (7). Exosomes derived from tumour cells have been associated with accelerating tumour growth (6,8) and invasiveness (9)(10)(11).…”