Recombinant Vesicular Stomatitis Virus Transduction of Dendritic Cells Enhances Their Ability to Prime Innate and Adaptive Antitumor Immunity |
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Authors: | Jeanette E Boudreau Byram W Bridle Kyle B Stephenson Kristina M Jenkins Jérôme Brunellière Jonathan L Bramson Brian D Lichty Yonghong Wan |
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Institution: | 1Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada;2Medical Sciences Program, McMaster University, Hamilton, Ontario, Canada |
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Abstract: | Dendritic cell (DC)–based vaccines are a promising strategy for tumor immunotherapy due to their ability to activate both antigen-specific T-cell immunity and innate immune effector components, including natural killer (NK) cells. However, the optimal mode of antigen delivery and DC activation remains to be determined. Using M protein mutant vesicular stomatitis virus (ΔM51-VSV) as a gene-delivery vector, we demonstrate that a high level of transgene expression could be achieved in ~70% of DCs without affecting cell viability. Furthermore, ΔM51-VSV infection activated DCs to produce proinflammatory cytokines (interleukin-12, tumor necrosis factor-α, and interferon (IFN)α/β), and to display a mature phenotype (CD40highCD86high major histocompatibility complex (MHC II)high). When delivered to mice bearing 10-day-old lung metastatic tumors, DCs infected with ΔM51-VSV encoding a tumor-associated antigen mediated significant control of tumor growth by engaging both NK and CD8+ T cells. Importantly, depletion of NK cells completely abrogated tumor destruction, indicating that NK cells play a critical role for this DC vaccine-induced therapeutic outcome. Our findings identify ΔM51-VSV as both an efficient gene-delivery vector and a maturation agent allowing DC vaccines to overcome immunosuppression in the tumor-bearing host. |
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