Recombinant vesicular stomatitis virus transduction of dendritic cells enhances their ability to prime innate and adaptive antitumor immunity.
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.
Boudreau
Jeanette E
JE
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Bridle
Byram W
BW
Stephenson
Kyle B
KB
Jenkins
Kristina M
KM
Brunellière
Jérôme
J
Bramson
Jonathan L
JL
Lichty
Brian D
BD
Wan
Yonghong
Y
D000818:Animals; D051940:B7-2 Antigen / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007110:Immunity, Active / Q000235:genetics / Q000502:physiology*; D007113:Immunity, Innate / Q000235:genetics / Q000502:physiology*; D007167:Immunotherapy / Q000379:methods; D018664:Interleukin-12 / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology / Q000628:therapy; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D012209:Rhabdoviridae / Q000235:genetics*; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D051940:B7-2 Antigen; D019013:CD40 Antigens; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12