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

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 2

Antigens delivered by theS. typhimurium type III secretion system are efficiently presented to CD8+ T cells.

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Antigens delivered by theS. typhimurium ...
(A) An HLA-A*0201–restricted CD8+ T cell clone specific for NY-ESO-1157–165 (clone 49) and an HLA-A*0201–restricted CD8+ T cell line specific for Influenza matrix58–66 (NW46-Flu) were cultured with SK-MEL-21 cells infected with S. typhimurium–NY-ESO-1, S. typhimurium–Flu matrix, or the S. typhimurium control strain, and specific IFN-γ secretion was assessed by ELISPOT assay. (B) CD8+ T cells derived from PBMCs of NY-ESO-1–expressing melanoma patients NW29 and NW634 were presensitized by CD4–CD8– PBMCs pulsed with NY-ESO-179–108 peptide as described in Methods. The induction of CD8+ T cells was analyzed by ELISPOT assay for recognition of autologous EBV-B cells pulsed with peptides or infected with S. typhimurium. These experiments were performed independently 3 times with similar results. Data are mean ± SD.