Prostate Tumor-Derived Exosomes Down-Regulate NKG2D Expression on Natural Killer Cells and CD8+ T Cells: Mechanism of Immune Evasion

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.

Telomeric repeat-containing RNA (TERRA) constitutes a nucleoprotein component of extracellular inflammatory exosomes

“…Tumor-derived exosomes promote tumor progression at many levels, either by suppressing antitumor immune responses (34) or by incorporating oncogenic materials (35). Whether telomeres and their derived RNA are involved in intercellular communication through exosome transport has not been studied.…”

Regulation of NKG2D+CD8+T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism

“…8 In prostate cancer patients, tumorderived exosomes downregulated NKG2D expression on circulating CD8 C T cells. 9 Recent NKG2D regulation studies showed that many cytokines influence NKG2D expression on CD8 C T and NK cells, including the NKG2D-promoting cytokines interleukin (IL)-2, IL-7, and IL-12 [10][11][12] ; the NKG2D-suppressing cytokines IL-4 and transforming growth factor-b; and interferon-g, at high levels. 13,14 However, the mechanisms of NKG2D regulation on CD8 C T cells remain poorly investigated.…”

DNAX-activating protein 10 co-stimulation enhances the anti-tumor efficacy of chimeric antigen receptor T cells

“…22,33 Cytokines such as IL-4 and TGF-β derived from the tumor microenvironment can down-regulate NKG2D expression on NK and CD8 + T cells and thereby dampen anti-tumor activit. 34–36 In contrast, cytokines that function through common γ chain receptors, including IL-2, IL-7, and IL-15, can support NKG2D expression on immune cell. 33 These findings prompted us to ascertain the importance of activating DAP10 signaling in T cells to facilitate tumor eradication.…”