Enhancement of DC vaccine potency by activating the PI3K/AKT pathway with a small interfering RNA targeting PTEN
| Autor: | Ye Hyeon Ahn, Tae Heung Kang, Tae Woo Kim, Keon Kim, Kyung Mi Lee, Jin Hee Kim, Young Ho Lee, Eun Young Choi, Hyun Cheol Bae, Kyung Hee Noh, Jin Seok Kim, Seok Ho Kim |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Small interfering RNA
Receptors CCR7 Cell Survival T cell Immunology Blotting Western bcl-X Protein C-C chemokine receptor type 7 Biology CD8-Positive T-Lymphocytes Transfection Cancer Vaccines Mice Phosphatidylinositol 3-Kinases Cell Movement Cell Line Tumor medicine Immunology and Allergy Tensin PTEN Animals RNA Small Interfering Protein kinase B PI3K/AKT/mTOR pathway Cells Cultured PTEN Phosphohydrolase Dendritic cell Dendritic Cells Neoplasms Experimental Flow Cytometry Xenograft Model Antitumor Assays Mice Inbred C57BL medicine.anatomical_structure Proto-Oncogene Proteins c-bcl-2 Cancer research biology.protein Lymph Nodes Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Immunology letters. 134(1) |
| ISSN: | 1879-0542 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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