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

Authors

  • Tae Heung Kang,

    1. Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University, Ansan, Gyeonggi, Korea
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  • Jin Hyup Lee,

    1. Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD
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  • Kyung Hee Noh,

    1. Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University, Ansan, Gyeonggi, Korea
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  • Hee Dong Han,

    1. Department of Advanced Materials, Korea Research Institute of Chemical Technology, Yuseong, Daejeon, Korea
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  • Byung Cheol Shin,

    1. Department of Advanced Materials, Korea Research Institute of Chemical Technology, Yuseong, Daejeon, Korea
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  • Eun Young Choi,

    1. Graduate Program of Immunology, Seoul National University College of Medicine, Seoul, Korea
    2. Center for Animal Resource Development, Seoul National University College of Medicine, Seoul, Korea
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  • Shiwen Peng,

    1. Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD
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  • Chien-Fu Hung,

    1. Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD
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  • T.-C. Wu,

    1. Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD
    2. Department of Obstetrics and Gynecology, Johns Hopkins Medical Institutions, Baltimore, MD
    3. Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD
    4. Department of Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, MD
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  • Tae Woo Kim

    Corresponding author
    1. Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University, Ansan, Gyeonggi, Korea
    2. Research Center for Women' s Diseases, Sookmyung Women' s University, Seoul, Korea
    • Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University, 516 Gojan-1 Dong, Ansan-Si, Gyeonggi-Do 425-707, South Korea
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    • Fax: +82-31-412-6718.


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. © 2007 Wiley-Liss, Inc.

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