Alphavirus-based DNA vaccine breaks immunological tolerance by activating innate antiviral pathways.
Cancer vaccines targeting 'self' antigens that are expressed at consistently high levels by tumor cells are potentially useful in immunotherapy, but immunological tolerance may block their function. Here, we describe a novel, naked DNA vaccine encoding an alphavirus replicon (self-replicating mRNA) and the self/tumor antigen tyrosinase-related protein-1. Unlike conventional DNA vaccines, this vaccine can break tolerance and provide immunity to melanoma. The vaccine mediates production of double-stranded RNA, as evidenced by the autophosphorylation of dsRNA-dependent protein kinase R (PKR). Double-stranded RNA is critical to vaccine function because both the immunogenicity and the anti-tumor activity of the vaccine are blocked in mice deficient for the RNase L enzyme, a key component of the 2',5'-linked oligoadenylate synthetase antiviral pathway involved in double-stranded RNA recognition. This study shows for the first time that alphaviral replicon-encoding DNA vaccines activate innate immune pathways known to drive antiviral immune responses, and points the way to strategies for improving the efficacy of immunization with naked DNA.
Leitner
Wolfgang W
WW
National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. wolfgang_leitner@nih.gov
Hwang
Leroy N
LN
deVeer
Michael J
MJ
Zhou
Aimin
A
Silverman
Robert H
RH
Williams
Bryan R G
BR
Dubensky
Thomas W
TW
Ying
Han
H
Restifo
Nicholas P
NP
D000524:Alphavirus / Q000235:genetics* / Q000276:immunology*; D000818:Animals; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D006801:Humans; D007108:Immune Tolerance; D007114:Immunization; D007167:Immunotherapy; D008545:Melanoma / Q000276:immunology* / Q000628:therapy; D008562:Membrane Glycoproteins; D051379:Mice; D008810:Mice, Inbred C57BL; D010088:Oxidoreductases; D010957:Plasmids / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000235:genetics / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics / Q000378:metabolism; D012093:Replicon / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D019496:Cancer Vaccines; D008562:Membrane Glycoproteins; D011506:Proteins; D012330:RNA, Double-Stranded; D019444:Vaccines, DNA; D010088:Oxidoreductases; C489799:TYRP1 protein, human; C079621:Tyrp1 protein, mouse; C064056:tyrosinase-related protein-1; D012324:RNA-Dependent RNA Polymerase