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
- Kang, Tae Heung; Lee, Jin Hyup; Noh, Kyung Hee; Han, Hee Dong; Shin, Byung Cheol; Choi, Eun Young; Peng, Shiwen; Hung, Chien-Fu; Wu, T. -C.; Kim, Tae Woo
- Issue Date
- Apr-2007
- Publisher
- WILEY-BLACKWELL
- Keywords
- dendritic cell; immunotherapy; siRNA; Sig/E7/LAMP-1; BAK; BAX
- Citation
- INTERNATIONAL JOURNAL OF CANCER, v.120, no.8, pp 1696 - 1703
- Pages
- 8
- Journal Title
- INTERNATIONAL JOURNAL OF CANCER
- Volume
- 120
- Number
- 8
- Start Page
- 1696
- End Page
- 1703
- URI
- https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/14702
- DOI
- 10.1002/ijc.22377
- ISSN
- 0020-7136
1097-0215
- 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-specilic 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. (c) 2007 Wiley-Liss, Inc.
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