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

Cancer Gene Therapy volume 8, pages 599–611 (2001)Cite this article

Abstract

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. Cancer Gene Therapy (2001) 8, 599–611

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Acknowledgements

This work was support by the Mildred Scheel Stiftung für Krebsforschung (M.Z.). We greatly appreciate the technical help by S. Hummel and M. Vitacolonna. We cordially thank B. A. Stocker (Stanford, CA, USA) for providing us with attenuated S. typhimurium , F. Momburg (Deutsches Krebsforschungszentrum, Heidelberg) for the pFM332.1p41 vector, and S. Matzku, Merck, Darmstadt, Germany for helpful suggestions and discussion during preparation of the manuscript.

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  1. Department of Tumor Progression and Immune Defense, German Cancer Research Center, Heidelberg, Germany

    Robert Weth, Oliver Christ & Margot Zöller

  2. Institute for Cell Biology, Tübingen, Germany

    Stefan Stevanovic

  3. Department of Applied Genetics, University of Karlsruhe, Karlsruhe, Germany

    Margot Zöller

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Weth, R., Christ, O., Stevanovic, S. et al. Gene delivery by attenuated Salmonella typhimurium : Comparing the efficacy of helper versus cytotoxic T cell priming in tumor vaccination. Cancer Gene Ther 8, 599–611 (2001). https://doi.org/10.1038/sj.cgt.7700352

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