Adenovirus-Mediated MUC1 gene transduction into human blood-derived dendritic cells

J Immunother. 2001 Jul-Aug;24(4):345-53. doi: 10.1097/00002371-200107000-00010.

Abstract

MUC1 protein is widely expressed on various human cancer cells and has a specific highly glycosylated core structure with multiple tandem repeats, which may include an immunogenic peptide sequence. The potency of MUC1 protein to induce human histocompatibility leukocyte antigen-class I-restricted cytotoxic T-lymphocyte (CTL) induction remains to be fully clarified in human beings. In the current study, we made MUC1-expressing human dendritic cells (DCs) using recombinant adenovirus vector. Adenovirus vector plasmid containing human MUC1 cDNA, pAdHM4-MUC1 was constructed using in vitro ligation with a shuttle vector, pHMCMV5. Adenovirus vector expressing MUC1 was generated by the transfection of PacI-digested recombinant vector plasmid into 293 cells. Human blood DCs were obtained from 7-day culture of monocytes with recombinant human (rh) granulocyte-macrophage (GM) colony-stimulating factor (CSF) and (rh)interleukin (IL)-4. Then, 1 x 10(6) DCs were incubated with viral supernatant at a multiplicity of infection of 200 for 24 h in the presence of rhGM-CSF and rhIL-4. Flow cytometric analysis showed that 30% to 40% of the transduced DCs expressed MUC I protein; by contrast, nontransduced or transduced DCs with mock virus expressed only small amounts of MUC1 protein. Adenovirus-mediated MUC1 gene transduction into DCs had no significant effect on DC surface marker expressions or functions such as mixed leukocyte reaction. Furthermore, MUCI-specific CD8+ CTLs could be induced from healthy donor blood lymphocytes using MUC1-expressing DCs as stimulators. These results suggested that MUC1 gene-transduced DCs are a functional and potent tool for triggering a CTL response against MUC1 cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics*
  • Animals
  • COS Cells
  • Cytotoxicity Tests, Immunologic
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism*
  • Gene Expression
  • Humans
  • Lymphocyte Culture Test, Mixed
  • Mucin-1 / genetics*
  • Mucin-1 / metabolism
  • Peptide Fragments / genetics*
  • Peptide Fragments / metabolism
  • T-Lymphocytes, Cytotoxic / immunology
  • Transduction, Genetic*
  • Tumor Cells, Cultured

Substances

  • MUC1 tandem repeat peptide
  • Mucin-1
  • Peptide Fragments