[HTML][HTML] Recombinant vesicular stomatitis virus transduction of dendritic cells enhances their ability to prime innate and adaptive antitumor immunity

JE Boudreau, BW Bridle, KB Stephenson, KM Jenkins… - Molecular Therapy, 2009 - cell.com
JE Boudreau, BW Bridle, KB Stephenson, KM Jenkins, J Brunellière, JL Bramson, BD Lichty
Molecular Therapy, 2009cell.com
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 …
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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