Abstract
Dendritic cell (DC)-based cancer vaccines have become important as an immunotherapeutics in generating anti-tumor immune responses. Due to a short lifespan of DCs, however, clinical application of current DC vaccines has been limited. Recently, activation of AKT/protein kinase B (PKB), a major effector of phosphatidylinositol 3-kinase (PI3K), has been reported as a critical factor in both activation and survival of DCs. We here improved the potency of a DC vaccine with a small interfering RNA (siRNA) targeting phosphatase and tensin homologue (PTEN), which is known to be a central negative regulator of the PI3K/AKT signal transduction cascade. Down-regulation of PTEN in DCs resulted in AKT dependent maturation, which in turn caused a significant up-regulation of surface expression in co-stimulatory molecules and the chemokine receptor, CCR7, leading to an increase of in vitro T cell activation activity and in vivo migration to a draining lymph node, respectively. Moreover, these PTEN siRNA-transfected DCs (DC/siPTEN) acquired an increased survival from the apoptotic death caused by GM-CSF deprivation or antigen-specific CD8+ T cell killing. Most importantly, DC/siPTEN generated more tumor antigen-specific CD8+ T cells and stronger anti-tumor effects in vaccinated mice than did control DCs (DC/siGFP). Thus, our data indicate that manipulation of the PI3K/AKT pathway via siRNA system could improve the efficacy of a DC-based tumor vaccine.
Original language | English |
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Pages (from-to) | 47-54 |
Number of pages | 8 |
Journal | Immunology Letters |
Volume | 134 |
Issue number | 1 |
DOIs | |
Publication status | Published - 2010 Nov 30 |
Bibliographical note
Funding Information:This work was supported by a grant from the Innovative Research Institute for Cell Therapy , Republic of Korea ( A062260 ), a grant from the Basic Research Program of the Korea Science & Engineering Foundation (No. R1-2006-000-10565-0 ), a grant from the National R&D Program for Cancer Control, Ministry of Health & Welfare ( 070355 ), and a grant R11-2005-017-03003-0 from the Research Center for Women's Diseases of KOSEF . K.M. Lee was supported by a grant from KICOS ( K20704000007-09A0500-00710 ).
Keywords
- AKT
- Dendritic cell
- Immunotherapy
- PI3K
- PTEN
- SiRNA
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology