Enhanced induction of dendritic cell maturation and HLA-A*0201-restricted CEA-specific CD8(+) CTL response by exosomes derived from IL-18 gene-modified CEA-positive tumor cells

J Mol Med (Berl). 2006 Dec;84(12):1067-76. doi: 10.1007/s00109-006-0102-0. Epub 2006 Sep 26.

Abstract

Dendritic cells (DC)-derived or tumor-derived exosomes are a population of nanometer sized membrane vesicles that can induce specific anti-tumor immunity. However, the immunogenic potential and efficiency of exosomes-based tumor vaccine are not satisfactory enough to achieve a curative effect in clinical trials. In this article we investigated whether IL-18 genetic modification of tumor cells can increase the efficacy of exosomes derived from IL-18 gene-modified tumor cells. We transfected carcinoembryonic antigen (CEA)-expressing tumor cells with a recombinant adenovirus encoding human IL-18 (AdhIL-18) and prepared the exosomes, Exo/IL-18, from IL-18 gene-modified tumor cells. We found that Exo/IL-18 naturally contain CEA and bioactive IL-18. Moreover, Exo-IL-18 are potent in chemoattracting DC and T cells, enhancing the proliferation and Th1 cytokine release of PBMC, and promoting the phenotypic and functional maturation of DC. Furthermore, Exo/IL-18-pulsed DC are quite potent to induce HLA-A*0201-restricted, CEA-specific CD8(+) CTL from the PBMC of HLA-A*0201 CEA(+) cancer patients in vitro. In almost all of these experiments, Exo/IL-18 show more potent functions than the conventionally prepared exosomes derived from parent tumor cells without IL-18 gene modification. Our findings suggest that Exo/IL-18 has more potent capability to induce specific anti-tumor immunity, and our strategy of IL-18 modification of exosomes is a feasible approach to develop exosomes-based tumor vaccines.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • CD8 Antigens / analysis
  • CD8-Positive T-Lymphocytes / immunology
  • Cancer Vaccines / immunology
  • Cancer Vaccines / therapeutic use*
  • Carcinoembryonic Antigen / immunology*
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Cell Proliferation
  • Cells, Cultured
  • Dendritic Cells / immunology*
  • Feasibility Studies
  • Female
  • HLA-A2 Antigen / genetics
  • HLA-A2 Antigen / immunology*
  • Humans
  • Interleukin-18 / genetics*
  • Leukocytes, Mononuclear / cytology
  • Leukocytes, Mononuclear / physiology
  • Lymphocyte Culture Test, Mixed
  • Male
  • T-Lymphocytes, Cytotoxic / immunology*
  • Transfection

Substances

  • CD8 Antigens
  • Cancer Vaccines
  • Carcinoembryonic Antigen
  • HLA-A2 Antigen
  • Interleukin-18