In vivo antigen delivery by a Salmonella typhimurium type III secretion system for therapeutic cancer vaccines
Hiroyoshi Nishikawa, … , Jorge E. Galán, Sacha Gnjatic
Hiroyoshi Nishikawa, … , Jorge E. Galán, Sacha Gnjatic
Published July 3, 2006
Citation Information: J Clin Invest. 2006;116(7):1946-1954. https://doi.org/10.1172/JCI28045.
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Research Article Vaccines

In vivo antigen delivery by a Salmonella typhimurium type III secretion system for therapeutic cancer vaccines

Abstract

Bacterial vectors may offer many advantages over other antigen delivery systems for cancer vaccines. We engineered a Salmonella typhimuriumvaccine strain to deliver the NY-ESO-1 tumor antigen (S. typhimurium–NY-ESO-1) through a type III protein secretion system. The S. typhimurium–NY-ESO-1 construct elicited NY-ESO-1–specific CD8+ and CD4+ T cells from peripheral blood lymphocytes ofcancer patients in vitro. Oral administration of S. typhimurium–NY-ESO-1 to mice resulted in the regression of established NY-ESO-1–expressing tumors. Intratumoral inoculation of S. typhimurium–NY-ESO-1 to NY-ESO-1–negative tumors resulted in delivery of antigen in vivo and led to tumor regression in the presence of preexisting NY-ESO-1–specific CD8+ T cells. Specific T cell responses against at least 2 unrelated tumor antigens not contained in the vaccine were observed, demonstrating epitope spreading. We propose that antigen delivery through the S. typhimuriumtype III secretion system is a promising novel strategy for cancer vaccine development.

Authors

Hiroyoshi Nishikawa, Eiichi Sato, Gabriel Briones, Li-Mei Chen, Mitsutoshi Matsuo, Yasuhiro Nagata, Gerd Ritter, Elke Jäger, Hideki Nomura, Shigeto Kondo, Isao Tawara, Takuma Kato, Hiroshi Shiku, Lloyd J. Old, Jorge E. Galán, Sacha Gnjatic

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Figure 1

S. typhimurium type III secretion system delivers recombinant NY-ESO-1 to target cells.

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S. typhimurium type III secretion system delivers rec...
(A) Diagram of relevant plasmids used in these studies. PsopE, SopE promoter. (B) A plasmid expressing NY-ESO-1 fused to the type III secretion and translocation signals of SopE (SopE–NY-ESO-1) was introduced into a ΔphoP ΔphoQS. typhimurium (WT) and an isogenic type III secretion-defective invA mutant (TTSS–). Whole cell lysates and cultured supernatants of these strains were then examined for the presence of the chimeric SopE–NY-ESO-1 protein by Western blotting as described in Methods. (C) Mouse CMS5a tumor cells were infected with S. typhimurium–NY-ESO-1 (S. typh–NY-ESO-1) or a translocation-defective strain, and the presence of SopE–NY-ESO-1 in the different fractions was examined as described in Methods. Blots containing the translocated protein fraction were reprobed for the host cell protein actin to verify equal loading of the samples. MW std., MW standard. (D) SK-MEL-21, a human melanoma cell line that does not express NY-ESO-1, was infected with S. typhimurium–NY-ESO-1 or the S. typhimurium control strain and examined by immunocytochemistry with anti–NY-ESO-1 mAb ES121. SK-MEL-37 served as a positive control of a human melanoma cell line with natural NY-ESO-1 expression.