Prostate tumor-derived exosomes down-regulate NKG2D expression on natural killer cells and CD8+ T cells: mechanism of immune evasion

PLoS One. 2014 Sep 30;9(9):e108925. doi: 10.1371/journal.pone.0108925. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism*
  • Castration
  • Cell Line
  • Down-Regulation / drug effects
  • Exosomes / metabolism*
  • Histocompatibility Antigens Class I / immunology
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Immune Evasion / drug effects
  • Intracellular Signaling Peptides and Proteins / immunology
  • Intracellular Signaling Peptides and Proteins / metabolism
  • K562 Cells
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism*
  • Leukocytes, Mononuclear / cytology
  • Leukocytes, Mononuclear / immunology
  • Male
  • NK Cell Lectin-Like Receptor Subfamily K / chemistry
  • NK Cell Lectin-Like Receptor Subfamily K / metabolism*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology*

Substances

  • Antibodies, Monoclonal
  • Histocompatibility Antigens Class I
  • Intracellular Signaling Peptides and Proteins
  • KLRK1 protein, human
  • NK Cell Lectin-Like Receptor Subfamily K

Grant support

This work was supported by grants from the Swedish Research Council (Grant no. C0217901, PW)(www.vr.se); the Swedish Cancer Society (Grant no. CAN2010-788, PW)(www.cancerfonden.se); the Cancer Research Foundation in Northern Sweden (Grant no. LP 10-1841 and LP 12-1940, ML) (www.cancerforskningsfonden.se); and Umeå University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.