Enhancement of DC vaccine potency by activating the PI3K/AKT pathway with a small interfering RNA targeting PTEN.

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.

Kim JH ，Kang TH ，Noh KH ，Kim SH ，Lee YH ，Kim KW ，Bae HC ，Ahn YH ，Choi EY ，Kim JS ，Lee KM ，Kim TW ... -  《-》

Enhancement of dendritic cell-based vaccine potency by anti-apoptotic siRNAs targeting key pro-apoptotic proteins in cytotoxic CD8(+) T cell-mediated cell death.

Kim JH ，Kang TH ，Noh KH ，Bae HC ，Kim SH ，Yoo YD ，Seong SY ，Kim TW ... -  《-》

Enhanced HER-2/neu-specific antitumor immunity by cotransduction of mouse dendritic cells with two genes encoding HER-2/neu and alpha tumor necrosis factor.

Chen Z ，Huang H ，Chang T ，Carlsen S ，Saxena A ，Marr R ，Xing Z ，Xiang J ... -  《CANCER GENE THERAPY》

Modification of dendritic cells with interferon-gamma-inducible protein-10 gene to enhance vaccine potency.

Kang TH ，Bae HC ，Kim SH ，Seo SH ，Son SW ，Choi EY ，Seong SY ，Kim TW ... -  《-》

The boosting effect of co-transduction with cytokine genes on cancer vaccine therapy using genetically modified dendritic cells expressing tumor-associated antigen.

Ojima T ，Iwahashi M ，Nakamura M ，Matsuda K ，Naka T ，Nakamori M ，Ueda K ，Ishida K ，Yamaue H ... -  《INTERNATIONAL JOURNAL OF ONCOLOGY》