Gene delivery by attenuated Salmonella typhimurium: comparing the efficacy of helper versus cytotoxic T cell priming in tumor vaccination

• Published in: Cancer gene therapy Vol. 8; no. 8; pp. 599 - 611
• Main Authors: Weth, R, Christ, O, Stevanovic, S, Zöller, M
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01-08-2001
• Subjects: Animals; Cancer Vaccines - administration & dosage; Cytotoxicity; Dendritic cells; Dendritic Cells - immunology; DNA Primers - chemistry; Gene therapy; Gene transfer; Gene Transfer Techniques; Glycoprotein gp100; gp100 Melanoma Antigen; Humans; Immunization; Immunosuppression; In Vitro Techniques; Interleukin 2; Invariant chain; Lymphocyte Activation; Lymphocytes T; Major histocompatibility complex; Melanoma; Melanoma, Experimental - immunology; Melanoma, Experimental - mortality; Membrane Glycoproteins - genetics; Mice; Mice, Inbred C57BL; Monocytes; Neoplasm Proteins - genetics; Oral administration; Polymerase Chain Reaction; Recombinant Fusion Proteins - genetics; Salmonella; Salmonella typhimurium; Salmonella typhimurium - genetics; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Helper-Inducer - immunology; Transcription; Vaccination; Vaccination - methods
• ISSN: 0929-1903; 1476-5500
• DOI: 10.1038/sj.cgt.7700352

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.