Enhancing dendritic cell vaccine potency by combining a BAK/BAX siRNA-mediated antiapoptotic strategy to prolong dendritic cell life with an intracellular strategy to target antigen to lysosomal compartments

Tae Heung Kang, Jin Hyup Lee, Kyung Hee Noh, Hee Dong Han, Byung Cheol Shin, Eun Young Choi, Shiwen Peng, Chien Fu Hung, T. C. Wu, Tae Woo Kim

Research output: Contribution to journalArticle

Abstract

Dendritic cell (DC)-based vaccines have become important in immunotherapeutics as a measure for generating antitumor immune responses. We have previously demonstrated that linkage of the antigen gene to a lysosomal targeting signal, a sorting signal of the lysosome-associated membrane protein type 1 (LAMP-1), enhances the potency of DC-based vaccines. DCs have a limited life span, hindering their long-term ability to prime antigen-specific T cells. In this study, we attempted to further improve the potency of a DC vaccine that targets human papilloma virus 16 (HPV16) E7 to a lysosomal compartment (DC-Sig/E7/LAMP-1) by combining a strategy to prolong DC life. We show that small interfering RNA-targeting Bak and Bax proteins can be used to allow transfected DCs to resist being killed by T cells. This is done by downregulating these proapoptotic proteins, which have been known as so-called gate keepers in mitochondria-mediated apoptosis. DCs expressing intact E7 or Sig/E7/LAMP-1 became resistant to attack by CD8+ T cells after transfection with BAK/BAX siRNA, leading to enhanced E7-specific T cell activation in vitro and in vivo. More importantly, vaccination with E7-presenting DCs transfected with BAK/BAX siRNA generated a strong therapeutic effect against an E7-expressing tumor in vaccinated mice, compared with DCs transfected with control siRNA. Our data indicate that a combination of strategies to enhance intracellular Ag processing and to prolong DC life may offer a promising strategy for improving DC vaccine potency.

Original languageEnglish (US)
Pages (from-to)1696-1703
Number of pages8
JournalInternational Journal of Cancer
Volume120
Issue number8
DOIs
StatePublished - Apr 15 2007

Keywords

  • BAK
  • BAX
  • Dendritic cell
  • Immunotherapy
  • Sig/E7/LAMP-1
  • siRNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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