Tumor vaccination by Salmonella typhimurium after transformation with a eukaryotic expression vector in mice: impact of a Salmonella typhimurium gene interfering with MHC class I presentation.
Transformed attenuated Salmonella typhimurium (ST) have been suggested as an efficient means of tumor vaccination. However, ST themselves might be immunosuppressive, and the question has arisen as to whether this impedes vaccination efficacy even if ST are transformed with a eukaryotic expression vector such that "tumor antigen" will be transcribed by the host. The question was evaluated using a mutant SL7207, where the yej operon, which interferes with MHC I-mediated presentation, had been inactivated (SL7207DeltayejE). Mice were vaccinated with SL7207 or SL7207DeltayejE transformed with a eukaryotic expression vector carrying the lacZ or the gp100 gene and later received lacZ-transfected RENCA or YC8 or gp100-expressing B16F1 tumor cells. In vaccinated mice, tumor growth started with a delay and some animals remained tumor-free; however, the tumor growth rate remained unaltered. No significant difference was seen between SL7207DeltayejE versus SL7207 vaccinated mice. The latter finding contrasted with ex vivo analyses where vaccination with SL7207DeltayejE, compared with SL7207, induced a significantly stronger response, including nonadaptive defense mechanisms. The failure to detect a superior vaccination efficacy of SL7207DeltayejE in vivo could be attributed to a stronger effect of the yej operon on MHC-mediated antigen presentation when driven by a prokaryotic promoter. Also, additional Salmonella genes apparently interfere with maintenance of a sustained immune response. Thus, the immunosuppressive yej operon affects innate and adaptive immunity. However, when ST are carriers for eukaryotic-expressed tumor antigens, yej does not severely hamper induction of an immune response.
Hummel
Susanne
S
Department of Tumor Progression and Tumor Defense, German Cancer Research Center, Heidelberg, Germany. m.zoeller@dkfz.de
Apte
Ron N
RN
Qimron
Udi
U
Vitacolonna
Mario
M
Porgador
Angel
A
Zöller
Margot
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D019496:Cancer Vaccines / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018076:DNA, Complementary / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology; D005434:Flow Cytometry / Q000379:methods; D005805:Genes, MHC Class I; D005822:Genetic Vectors; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007167:Immunotherapy; D066298:In Vitro Techniques; D015979:Killer Cells, Lymphokine-Activated / Q000166:cytology; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000166:cytology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism; D009154:Mutation; D012486:Salmonella typhimurium / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology; D013997:Time Factors
D000911:Antibodies, Monoclonal; D019496:Cancer Vaccines; D018076:DNA, Complementary; D007166:Immunosuppressive Agents