Abstract
Background: Dendritic cell (DC)-based vaccines have become a promising modality in cancer immunotherapy. However, their ability to initiate tumor antigen-specific T cell immunity is limited in various negative-feedback mechanisms. The rapid down-regulation of chemokines, such as the interferon inducible protein of 10 kDa (IP-10), which chemoattracts activated antigen-specific CD8+ T cells, would represent negative-feedback regulation. Therefore, we attempted to improve DC vaccine potency by introducing the IP-10 gene retrovirally aiming to replenish the chemoattractive activity of DCs. Methods: We introduced IP-10 gene into DC2.4 cells, referred to as DC-IP10, using a retroviral system. Nonsecretable mIP-10-expressing DCs (DC-mIP10) were also prepared to evaluate the effects of secretion in IP-10-mediated modulation of DC biology. Additionally, in vitro and in vivo activation of antigen-specific T lymphocytes and in vivo anti-tumor effects induced by DC-IP10 or DC-mIP10 were determined. Results: The modification of DC2.4 cells with the IP-10 gene resulted in the secretion of functionally chemoattractive IP-10 and, unexpectedly, a significant up-regulation of surface expression in co-stimulatory molecules, such as CD40 and CD80, compared to that of DCs with vector control (DC-no insert). DC-mIP10 also displayed the partially matured phenotypes but failed to recruit antigen-specific T cells in an in vitro cell culture system. Consistently, DC-IP10 generated more tumor antigen-specific CD8+ T cells and stronger anti-tumor effects in vaccinated mice than did control DCs and DC-mIP10. Conclusions: The results obtained provide the groundwork for a future clinical translation of the chemokine-based genetic modification of DCs to increase their vaccine potency.
Original language | English |
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Pages (from-to) | 889-898 |
Number of pages | 10 |
Journal | Journal of Gene Medicine |
Volume | 11 |
Issue number | 10 |
DOIs | |
Publication status | Published - 2009 |
Keywords
- Cancer vaccine
- Chemokine
- Dendritic cell
- IP-10
- Immunotherapy
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Genetics
- Drug Discovery
- Genetics(clinical)