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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 (DeltaM51-VSV) as a gene-delivery vector, we demonstrate
that a high level of transgene expression could be achieved in approximately 70% of
DCs without affecting cell viability. Furthermore, DeltaM51-VSV infection activated
DCs to produce proinflammatory cytokines (interleukin-12, tumor necrosis factor-alpha,
and interferon (IFN)alpha/beta), and to display a mature phenotype (CD40(high)CD86(high)
major histocompatibility complex (MHC II)(high)). When delivered to mice bearing 10-day-old
lung metastatic tumors, DCs infected with DeltaM51-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 DeltaM51-VSV as both an efficient gene-delivery vector
and a maturation agent allowing DC vaccines to overcome immunosuppression in the tumor-bearing
host.