RNA interference-mediated silencing of Foxo3 in antigen-presenting cells as a strategy for the enhancement of DNA vaccine potency
| Autor: | Der-Yuan Chen, Lan Jl, Peng Yt, Wang St, Chia Che Chang, Tu Cf, Meng-Chi Yen, Chi-Chen Lin, Ching-Liang Chu |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
T-Lymphocytes
Genetic enhancement Genetic Vectors Antigen-Presenting Cells Biology Cancer Vaccines Cell Line DNA vaccination Small hairpin RNA Mice RNA interference Chlorocebus aethiops Vaccines DNA Genetics Animals Humans Gene silencing Cytotoxic T cell RNA Small Interfering Antigen-presenting cell Molecular Biology Mice Inbred C3H Forkhead Box Protein O3 Forkhead Transcription Factors Dendritic Cells Biolistics Genes erbB-2 Virology Mice Inbred C57BL Urinary Bladder Neoplasms Cancer research Molecular Medicine RNA Interference Cancer vaccine |
| Zdroj: | Gene Therapy. 18:372-383 |
| ISSN: | 1476-5462 0969-7128 |
| Popis: | The transcription factor Forkhead box O3 (Foxo3) has a critical role in suppressing the expansion of antigen-specific effector T-cell populations; hence, Foxo3 is a potential target for enhancing the antitumor immunity of cancer vaccines. In this report, we evaluated the potential of RNA interference (RNAi)-mediated silencing of Foxo3 in antigen-presenting cells as an adjuvant for HER2/neu DNA cancer vaccines. Bicistronic plasmids expressing the N-terminal extracellular domain of human HER-2/neu and the Foxo3 short hairpin RNA (hN'-neu-Foxo3 shRNA) or the scrambled control (hN'-neu-scramble shRNA) were subcutaneously injected into mice by gene gun administration to elicit antitumor immunity against p185neu-overexpressing MBT-2 bladder tumor cells. We found that mice treated with hN'-neu-Foxo3 shRNA showed greater reductions in tumor growth and longer survival times than mice treated with hN'-neu-scramble shRNA, indicating that the silencing of Foxo3 enhanced the antitumor efficacy of the HER-2/neu cancer vaccine. Cytotoxicity analyses further revealed that the Foxo3 shRNA-enhanced antitumor effect was associated with significant increases in the number of functional CD8(+) T cells and in the levels of cytotoxic T lymphocytes activity. Interleukin-6 was induced by hN'-neu-Foxo3 shRNA treatment but did not have a critical role in the antitumor effect of the hN'-neu-Foxo3 shRNA vaccine. Moreover, in vivo lymphocyte depletion analyses confirmed that the antitumor efficacy of the hN'-neu-Foxo3 shRNA vaccine depended on functional CD8(+) T cells. Finally, Foxo3 suppression was shown to markedly improve the effect of the HER-2/neu DNA vaccine in limiting the growth and lung metastases of MBT-2 cells. Overall, these results support RNAi-mediated silencing of Foxo3 as an effective strategy to enhance the therapeutic antitumor effect of HER-2/neu DNA vaccines against p185neu-positive tumors. |
| Databáze: | OpenAIRE |
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