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
Jin Hee
JH
Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, South Korea.
Kang
Tae Heung
TH
Noh
Kyung Hee
KH
Kim
Seok-Ho
SH
Lee
Young-Ho
YH
Kim
Keon Woo
KW
Bae
Hyun Cheol
HC
Ahn
Ye-Hyeon
YH
Choi
Eun Young
EY
Kim
Jin-Seok
JS
Lee
Kyung-Mi
KM
Kim
Tae Woo
TW
D000818:Animals; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D002470:Cell Survival; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics*; D054400:Receptors, CCR7 / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000378:metabolism
D019496:Cancer Vaccines; C515371:Ccr7 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D054400:Receptors, CCR7; D051020:bcl-X Protein; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase