Enhancement of DNA vaccine potency by linkage of antigen gene to a gene encoding the extracellular domain of Fms-like tyrosine kinase 3-ligand

C. F. Hung, K. F. Hsu, W. F. Cheng, C. Y. Chai, L. He, M. Ling, T. C. Wu

Research output: Contribution to journalArticle

Abstract

Recently, Flt3 (Fms-like tyrosine kinase 3)-ligand has been identified as an important cytokine for the generation of professional antigen-presenting cells (APCs), particularly dendritic cells (DCs). A recombinant chimera of the extracellular domain of Flt3-ligand (FL) linked to a model antigen may potentially target the antigen to DCs and their precursor cells. Using human papillomavirus-16 E7 as a model antigen, we evaluated the effect of linkage to FL on the potency of antigen-specific immunity generated by naked DNA vaccines administered intradermally via gene gun. We found that vaccines containing chimeric FL-E7 fusion genes significantly increased the frequency of E7-specific CD8+ T cells relative to vaccines containing the wild-type E7 gene. In vitro studies indicated that cells transfected with FL-E7 DNA presented E7 antigen through the MHC class I pathway more efficiently than wild-type E7 DNA. Furthermore, bone marrow-derived DCs pulsed with cell lysates containing FL-E7 fusion protein presented E7 antigen through the MHC class I pathway more efficiently than DCs pulsed with cell lysates containing wild-type E7 protein. More importantly, this fusion converted a less effective vaccine into one with significant potency against established E7-expressing metastatic tumors. The FL-E7 fusion vaccine mainly targeted CD8+ T cells, and antitumor effects were completely CD4 independent. These results indicate that fusion of a gene encoding the extracellular domain of FL to an antigen gene may greatly enhance the potency of DNA vaccines via CD8-dependent pathways.

Original languageEnglish (US)
Pages (from-to)1080-1088
Number of pages9
JournalCancer Research
Volume61
Issue number3
StatePublished - Mar 6 2001

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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