Transgene expression in dendritic cells to induce antigen-specific cytotoxic T cells in healthy donors

Cancer Gene Ther. Jul-Aug 1998;5(4):236-46.

Abstract

Immunization with specific tumor-associated antigen (Ag) (TAA)-pulsed dendritic cells (DC) has proven to be efficacious in a variety of animal models and is being investigated for the treatment of cancer patients. Use of DC pulsed with specific peptides or transfected with TAA genes has been a focused area of investigation for the induction of potent tumor and viral immune responses. In this study we demonstrate transgene expression, including expression of the MART-1 gene, in DC transfected with plasmid DNA and cationic liposome complexes. These transiently transfected DC, derived from healthy donor monocytes cultured with granulocyte macrophage colony-stimulating factor and interleukin-4, express the transgene and can stimulate naive CD8+ T cells to elicit an antitumor immune response. These cytotoxic T lymphocytes (CTL) were capable of recognizing both known and unknown TAA epitopes and were able to exhibit cytolytic activity against human histocompatibility leukocyte Ag-matched tumor cells expressing the Ag. In addition to their cytolytic function, the CTL displayed an oligoclonal T-cell receptor repertoire, indicating that the presented Ag induced alterations in the T-cell population. The ability to induce tumor-specific CTL in vitro using gene-modified DC transiently expressing TAAs demonstrates the potential use of these Ag-presenting cells to generate future in vivo cancer vaccine strategies.

MeSH terms

  • Antigens, Neoplasm
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Carcinoembryonic Antigen / genetics*
  • Carcinoembryonic Antigen / metabolism
  • Cells, Cultured
  • Chloramphenicol O-Acetyltransferase / genetics
  • Chloramphenicol O-Acetyltransferase / metabolism
  • Dendritic Cells / cytology
  • Dendritic Cells / drug effects
  • Dendritic Cells / physiology*
  • Dependovirus / genetics
  • Genes, MHC Class I
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Humans
  • Interleukin-4 / pharmacology
  • Liposomes
  • MART-1 Antigen
  • Major Histocompatibility Complex
  • Monocytes
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Receptors, Antigen, T-Cell / drug effects
  • Receptors, Antigen, T-Cell / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • T-Lymphocytes, Cytotoxic / immunology*
  • Transfection
  • Transgenes

Substances

  • Antigens, Neoplasm
  • Carcinoembryonic Antigen
  • Liposomes
  • MART-1 Antigen
  • MLANA protein, human
  • Neoplasm Proteins
  • Receptors, Antigen, T-Cell
  • Recombinant Proteins
  • Interleukin-4
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Chloramphenicol O-Acetyltransferase