Gene delivery by attenuated Salmonella typhimurium: Comparing the efficacyof helper versus cytotoxic T cell priming in tumor vaccination

Using the murine B16F1 melanoma, we compared a CTL- versus helper T cell (T H)-directed vaccination approach. Mice were either orally vaccinated with a ttenuated Salmonella typhimurium (SL) or subcutaneously with dendritic cell s (DCs) loaded with gp100 peptides predicted to bind to H2 - Kb/H2 - Db mol ecules. 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 /li. Transcription of these genes in vivo has been readily observed in mono cytes and DC. Retardation of B16F1 growth was more efficiently achieved by vaccination with SL-gp100 than with DC. Vaccination with SL-gp100/li aiming at preferential presentation by MHC II molecules provided some further imp rovement 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 conc omitantly received IL2. Notably, prophylactic, compared to therapeutic, vac cination had no additional impact on survival time/rate. This was due to a striking decrease in frequencies of gp100-specific TH, CTL, and cytokine-ex pressing cells during tumor growth. Thus, the efficacy of vaccination was l imited by tumor-induced immunosuppression. Our data demonstrate the oral ro ute of vaccination via Salmonella as a most convenient transfer regimen and confirm the superiority of protocols aiming at preferential activation of TH.