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

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 (C) 2010 Elsevier B V All rights reserved