Alphaviral vector-transduced dendritic cells are successful therapeutic vaccines against neu-overexpressing tumors in wild-type mice.
While dendritic cell (DC) vaccines can protect hosts from tumor challenge, their ability to effectively inhibit the growth of established tumors remains indeterminate. Previously, we have shown that human DCs transduced with Venezuelan equine encephalitis virus replicon particles (VRPs) were potent stimulators of antigen-specific T cells in vitro. Therefore, we investigated the ability of VRP-transduced DCs (VRP-DCs) to induce therapeutic immunity in vivo against tumors overexpressing the neu oncoprotein. Transduction of murine DCs with VRPs resulted in high-level transgene expression, DC maturation and secretion of proinflammatory cytokines. Vaccination with VRP-DCs expressing a truncated neu oncoprotein induced robust neu-specific CD8(+) T cell and anti-neu IgG responses. Furthermore, a single vaccination with VRP-DCs induced the regression of large established tumors in wild-type mice. Interestingly, depletion of CD4(+), but not CD8(+), T cells completely abrogated inhibition of tumor growth following vaccination. Taken together, our results demonstrate that VRP-DC vaccines induce potent immunity against established tumors, and emphasize the importance of the generation of both CD4(+) T cell and B cell responses for efficient tumor inhibition. These findings provide the rationale for future evaluation of VRP-DC vaccines in the clinical setting.
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
Timothy P
TP
Moran
Joseph E
JE
Burgents
Brian
B
Long
Ivana
I
Ferrer
Elizabeth M
EM
Jaffee
Roland M
RM
Tisch
Robert E
RE
Johnston
Jonathan S
JS
Serody
D016475:3T3 Cells; D000524:Alphavirus / Q000235:genetics; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D041681:NIH 3T3 Cells; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
D019496:Cancer Vaccines; D007074:Immunoglobulin G; D018719:Erb-b2 Receptor Tyrosine Kinases