Abstract
Tumor-derived exosomes, which are nanometer-sized extracellular vesicles of endosomal origin, have emerged as promoters of tumor immune evasion but their role in prostate cancer (PC) progression is poorly understood. In this study, we investigated the ability of prostate tumor-derived exosomes to downregulate NKG2D expression on natural killer (NK) and CD8+ T cells. NKG2D is an activating cytotoxicity receptor whose aberrant loss in cancer plays an important role in immune suppression. Using flow cytometry, we found that exosomes produced by human PC cells express ligands for NKG2D on their surface. The NKG2D ligand-expressing prostate tumor-derived exosomes selectively induced downregulation of NKG2D on NK and CD8+ T cells in a dose-dependent manner, leading to impaired cytotoxic function in vitro. Consistent with these findings, patients with castration-resistant PC (CRPC) showed a significant decrease in surface NKG2D expression on circulating NK and CD8+ T cells compared to healthy individuals. Tumor-derived exosomes are likely involved in this NKG2D downregulation, since incubation of healthy lymphocytes with exosomes isolated from serum or plasma of CRPC patients triggered downregulation of NKG2D expression in effector lymphocytes. These data suggest prostate tumor-derived exosomes as down-regulators of the NKG2D-mediated cytotoxic response in PC patients, thus promoting immune suppression and tumor escape.
Highlights
Exosomes are small (30- to 100-nm) membrane vesicles of endocytic origin that are actively secreted from most cell types
Variable NKG2D-ligand expression was observed in different prostate cancer (PC) lines, but all prostate tumor cells examined were positive for UL-16 binding proteins (ULBPs)-2 and MICA/B ligands (Figure 1). 22Rv1 cells expressed high levels of ULBP-2 and MICA/B ligands, and they were used for exosome isolation and in the experiments that followed (Figure 1)
We found that circulating exosomes in PC patients selectively induce downregulation of the activating receptor NKG2D on natural killer (NK) cells and CD8+ T cells, and that this most likely impairs lymphocyte cytotoxic function and promote tumor immune escape
Summary
Exosomes are small (30- to 100-nm) membrane vesicles of endocytic origin that are actively secreted from most cell types. They contain a variety of biologically active molecules such as proteins, mRNAs, and microRNAs reflecting the cell of origin, and they probably mediate a range of local and systematic functions [1,2,3,4]. Tumor cells produce large amounts of exosomes, which has been shown in vitro and by purification from plasma, ascites, and pleural effusions from cancer patients [5,6,7,8]. Ligands for NKG2D, the MHC class I chain-related (MIC)
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