Dendritic cell-derived exosomes promote natural killer cell activation and proliferation: a role for NKG2D ligands and IL-15Ralpha

PLoS One. 2009;4(3):e4942. doi: 10.1371/journal.pone.0004942. Epub 2009 Mar 25.

Abstract

Dendritic cell (DC) derived-exosomes (Dex) are nanomeric vesicles harboring functional MHC/peptide complexes promoting T cell-dependent tumor rejection. In the first Phase I trial using peptide-pulsed Dex, the observation of clinical regressions in the absence of T cell responses prompted the search for alternate effector mechanisms. Mouse studies unraveled the bioactivity of Dex on NK cells. Indeed, Dex promoted an IL-15Ralpha- and NKG2D-dependent NK cell proliferation and activation respectively, resulting in anti-metastatic effects mediated by NK1.1(+) cells. In humans, Dex express functional IL-15Ralpha which allow proliferation and IFNgamma secretion by NK cells. In contrast to immature DC, human Dex harbor NKG2D ligands on their surface leading to a direct engagement of NKG2D and NK cell activation ex vivo. In our phase I clinical trial, we highlight the capacity of Dex based-vaccines to restore the number and NKG2D-dependent function of NK cells in 7/14 patients. Altogether, these data provide a mechanistic explanation on how Dex may stimulate non MHC restricted-anti-tumor effectors and induce tumor regression in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cancer Vaccines
  • Cell Line
  • Cell Proliferation
  • Dendritic Cells / cytology*
  • Exosomes / immunology*
  • Exosomes / transplantation
  • Humans
  • Immunotherapy / methods
  • Interleukin-15 Receptor alpha Subunit / immunology*
  • Killer Cells, Natural / cytology
  • Killer Cells, Natural / immunology*
  • Ligands
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • NK Cell Lectin-Like Receptor Subfamily K / immunology*

Substances

  • Cancer Vaccines
  • Interleukin-15 Receptor alpha Subunit
  • KLRK1 protein, human
  • Klrk1 protein, mouse
  • Ligands
  • NK Cell Lectin-Like Receptor Subfamily K