Abstract
Although CD4+ Type-1T helper (Th1) cells secreting interferon-γ (IFN-γ) appear to play an essential role in promoting durable antitumor immunity, we have previously shown that patients with cancer exhibit dysfunctional Th1-type responses against epitopes derived from tumor antigens, such as MAGE-A6. Here, we engineered human dendritic cells (DCs) to secrete high levels of the IFN-γ-inducing cytokines, interleukin (IL)-12p70 and IL-18, via recombinant adenoviral infection to generate an in vitro stimulus capable of promoting previously deficient patient Th1-type responses. Dendritic cells co-infected with Ad.IL-12 and Ad.IL-18 (DC.IL-12/18) were more effective at stimulating MAGE-A6-specific Th1-type CD4+ T-cell responses than DCs infected with either of the cytokine vectors alone, control Ad.Ψ5 virus or uninfected DCs. Furthermore, we show that DC.IL-12/18 loaded with recombinant MAGE-A6 protein (rMAGE) and used as in vitro stimulators promote Th1-type immunity that is frequently directed against multiple MAGE-A6-derived epitopes. The superiority of DC.IL-12/18-based stimulations in melanoma patients was independent of disease stage or current disease status. Based on these results, we believe this modality may prove clinically useful as a vaccine platform to promote the recovery of tumor antigen-specific, Th1-type CD4+ T-cell responses in patients with cancer.
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Acknowledgements
We thank Drs William Chambers, Nikola Vujanovic and Amy Wesa for their careful review and helpful comments provided during the generation of this manuscript. This work was supported by the National Institutes of Health (NIH) Grants RO1 CA57840 and P01 CA100327 (to WJS).
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Vujanovic, L., Ranieri, E., Gambotto, A. et al. IL-12p70 and IL-18 gene-modified dendritic cells loaded with tumor antigen-derived peptides or recombinant protein effectively stimulate specific Type-1 CD4+ T-cell responses from normal donors and melanoma patients in vitro. Cancer Gene Ther 13, 798–805 (2006). https://doi.org/10.1038/sj.cgt.7700964
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DOI: https://doi.org/10.1038/sj.cgt.7700964
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