Targeting human papillomavirus type 16 E7 to the endosomal/lysosomal compartment enhances the antitumor immunity of DNA vaccines against murine human papillomavirus type 16 E7-expressing tumors

Hongxiu Ji, Tian Li Wang, Chien Hung Chen, Sara I. Pai, Chien Fu Hung, Ken Yu Lin, Robert J. Kurman, Drew M. Pardoll, T. C. Wu

Research output: Contribution to journalArticle

207 Citations (Scopus)

Abstract

DNA vaccination is an attractive approach for tumor immunotherapy because of its stability and simplicity of delivery. Advances demonstrate that helper T cell responses play a critical role in initiating immune responses. The aim of the current study is to test whether targeting HPV-16 E7 to the endosomal/lysosomal compartment can enhance the potency of DNA vaccines. We linked the lysosome-associated membrane protein 1 (LAMP-1) to HPV-E7 to construct a chimeric DNA, Sig/E7/LAMP-1 DNA. For in vivo tumor prevention experiments, mice were vaccinated with E7 DNA or Sig/E7/LAMP-1 DNA via gene gun, followed by tumor challenge. For in vivo tumor regression experiments, mice were first challenged with tumor cells and then vaccinated with E7-DNA or Sig/E7/LAMP-1 DNA. Intracellular cytokine staining with flow cytometry analysis, cytotoxic T lymphocyte (CTL) assays, enzyme-linked immunoabsorbent assay (ELISA), and enzyme-linked immunospot (ELISPOT) assays were used for in vitro E7-specific immunological studies. In both tumor prevention and tumor regression assays, Sig/E7/LAMP-1 DNA generated greater antitumor immunity than did wild-type E7 DNA. In addition, mice vaccinated with Sig/E7/LAMP-1 DNA had greater numbers of E7-specific CD4+ helper T cells, higher E7-specific CTL activity, and greater numbers of CD8+ T cell precursors than did mice vaccinated with Sig/E7 or wild-type E7 DNA. Sig/E7 generated a stronger E7-specific antibody response than did Sig/E7/LAMP-1 or wild-type E7 DNA. Our results indicate that linkage of the antigen gene to an endosomal/lysosomal targeting signal may greatly enhance the potency of DNA vaccines.

Original languageEnglish (US)
Pages (from-to)2727-2740
Number of pages14
JournalHuman Gene Therapy
Volume10
Issue number17
DOIs
StatePublished - Nov 20 1999

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DNA Vaccines
Human papillomavirus 16
Lysosome-Associated Membrane Glycoproteins
Immunity
DNA
Neoplasms
Vaccine Potency
Cytotoxic T-Lymphocytes
Helper-Inducer T-Lymphocytes
T-Lymphoid Precursor Cells
Enzyme-Linked Immunospot Assay
Firearms
Enzyme Assays
Immunotherapy
Genes
Antibody Formation
Flow Cytometry
Vaccination

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Targeting human papillomavirus type 16 E7 to the endosomal/lysosomal compartment enhances the antitumor immunity of DNA vaccines against murine human papillomavirus type 16 E7-expressing tumors. / Ji, Hongxiu; Wang, Tian Li; Chen, Chien Hung; Pai, Sara I.; Hung, Chien Fu; Lin, Ken Yu; Kurman, Robert J.; Pardoll, Drew M.; Wu, T. C.

In: Human Gene Therapy, Vol. 10, No. 17, 20.11.1999, p. 2727-2740.

Research output: Contribution to journalArticle

Ji, Hongxiu ; Wang, Tian Li ; Chen, Chien Hung ; Pai, Sara I. ; Hung, Chien Fu ; Lin, Ken Yu ; Kurman, Robert J. ; Pardoll, Drew M. ; Wu, T. C. / Targeting human papillomavirus type 16 E7 to the endosomal/lysosomal compartment enhances the antitumor immunity of DNA vaccines against murine human papillomavirus type 16 E7-expressing tumors. In: Human Gene Therapy. 1999 ; Vol. 10, No. 17. pp. 2727-2740.
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abstract = "DNA vaccination is an attractive approach for tumor immunotherapy because of its stability and simplicity of delivery. Advances demonstrate that helper T cell responses play a critical role in initiating immune responses. The aim of the current study is to test whether targeting HPV-16 E7 to the endosomal/lysosomal compartment can enhance the potency of DNA vaccines. We linked the lysosome-associated membrane protein 1 (LAMP-1) to HPV-E7 to construct a chimeric DNA, Sig/E7/LAMP-1 DNA. For in vivo tumor prevention experiments, mice were vaccinated with E7 DNA or Sig/E7/LAMP-1 DNA via gene gun, followed by tumor challenge. For in vivo tumor regression experiments, mice were first challenged with tumor cells and then vaccinated with E7-DNA or Sig/E7/LAMP-1 DNA. Intracellular cytokine staining with flow cytometry analysis, cytotoxic T lymphocyte (CTL) assays, enzyme-linked immunoabsorbent assay (ELISA), and enzyme-linked immunospot (ELISPOT) assays were used for in vitro E7-specific immunological studies. In both tumor prevention and tumor regression assays, Sig/E7/LAMP-1 DNA generated greater antitumor immunity than did wild-type E7 DNA. In addition, mice vaccinated with Sig/E7/LAMP-1 DNA had greater numbers of E7-specific CD4+ helper T cells, higher E7-specific CTL activity, and greater numbers of CD8+ T cell precursors than did mice vaccinated with Sig/E7 or wild-type E7 DNA. Sig/E7 generated a stronger E7-specific antibody response than did Sig/E7/LAMP-1 or wild-type E7 DNA. Our results indicate that linkage of the antigen gene to an endosomal/lysosomal targeting signal may greatly enhance the potency of DNA vaccines.",
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