Gene delivery by attenuated Salmonella typhimurium: comparing the efficacy of helper versus cytotoxic T cell priming in tumor vaccination.
Using the murine B16F1 melanoma, we compared a CTL- versus helper T cell (TH)-directed vaccination approach. Mice were either orally vaccinated with attenuated Salmonella typhimurium (SL) or subcutaneously with dendritic cells (DCs) loaded with gp100 peptides predicted to bind to H2-Kb/H2-Db molecules. SL were transformed with the murine gp100 cDNA (SL-gp100) or with a fusion construct of gp100 and a fragment of invariant chain cDNA (SL-gp100/Ii). Transcription of these genes in vivo has been readily observed in monocytes and DC. Retardation of B16F1 growth was more efficiently achieved by vaccination with SL-gp100 than with DC. Vaccination with SL-gp100/Ii aiming at preferential presentation by MHC II molecules provided some further improvement due to a stronger expansion of TH and CTL. The importance of help was further sustained by a prolongation of the survival time when mice concomitantly received IL2. Notably, prophylactic, compared to therapeutic, vaccination had no additional impact on survival time/rate. This was due to a striking decrease in frequencies of gp100-specific TH, CTL, and cytokine-expressing cells during tumor growth. Thus, the efficacy of vaccination was limited by tumor-induced immunosuppression. Our data demonstrate the oral route of vaccination via Salmonella as a most convenient transfer regimen and confirm the superiority of protocols aiming at preferential activation of TH.
Weth
R
R
Department of Tumor Progression and Immune Defense, German Cancer Research Center, Heidelberg, Germany.
Christ
O
O
Stevanovic
S
S
Zöller
M
M
D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage*; D017931:DNA Primers / Q000737:chemistry; D003713:Dendritic Cells / Q000276:immunology; D018014:Gene Transfer Techniques; D006801:Humans; D066298:In Vitro Techniques; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000276:immunology* / Q000401:mortality; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011993:Recombinant Fusion Proteins / Q000235:genetics; D012486:Salmonella typhimurium / Q000235:genetics*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014611:Vaccination / Q000379:methods; D058951:gp100 Melanoma Antigen
D019496:Cancer Vaccines; D017931:DNA Primers; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C548637:PMEL protein, human; C548642:Pmel protein, mouse; D011993:Recombinant Fusion Proteins; D058951:gp100 Melanoma Antigen