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Intravesical Ty21a Vaccine Promotes Dendritic Cells and T Cell-Mediated Tumor Regression in the MB49 Bladder Cancer Model.

Abstract
Preclinical data show that intravesical instillation of Ty21a/Vivotif, a commercial vaccine against typhoid fever, is an effective alternative option to standard Bacillus Calmette-Guérin (BCG) immunotherapy for non-muscle-invasive bladder cancer (NMIBC). Here, we characterized the inflammatory effects of Ty21a on the bladder and investigated the immune mechanisms underlying tumor regression toward the use of this bacterial vaccine in NMIBC patients. MB49 bladder tumor-bearing mice had significantly improved survival after intravesical instillations of Ty21a doses of 106 to 108 colony-forming units. By IHC and morphology, both BCG and Ty21a instillations were associated with bladder inflammation, which was decreased with the use of low, but effective doses of Ty21a. Flow-cytometry analysis showed a significant infiltration of T cells, natural killer (NK) cells, and myeloid cells, compared with controls, after a single dose of Ty21a, whereas this was only observed after multiple doses of BCG. The induced myeloid cells were predominantly neutrophils and Ly6C+CD103+ dendritic cells (DC), the latter being significantly more numerous after instillation of Ty21a than BCG. Ex vivo infection of human leukocytes with Ty21a, but not BCG, similarly significantly increased DC frequency. CD4+ and CD8+ T cells, but not NK cells nor neutrophils, were required for effective bladder tumor regression upon Ty21a treatment. Thus, the generation of antitumor adaptive immunity was identified as a key process underlying Ty21a-mediated treatment efficacy. Altogether, these results demonstrate mechanisms behind intravesical Ty21a therapy and suggest its potential as a safe and effective treatment for NMIBC patients.
AuthorsSonia Domingos-Pereira, Karthik Sathiyanadan, Stefano La Rosa, Lenka Polák, Mathieu F Chevalier, Paul Martel, Rim Hojeij, Laurent Derré, Jacques-Antoine Haefliger, Patrice Jichlinski, Denise Nardelli-Haefliger
JournalCancer immunology research (Cancer Immunol Res) Vol. 7 Issue 4 Pg. 621-629 (04 2019) ISSN: 2326-6074 [Electronic] United States
PMID30696629 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright©2019 American Association for Cancer Research.
Chemical References
  • Polysaccharides, Bacterial
  • Ty21a typhoid vaccine
  • Typhoid-Paratyphoid Vaccines
Topics
  • Administration, Intravesical
  • Animals
  • Cell Line, Tumor
  • Dendritic Cells (immunology)
  • Disease Models, Animal
  • Female
  • Humans
  • Leukocytes (immunology)
  • Mice
  • Mice, Inbred C57BL
  • Mycobacterium bovis
  • Polysaccharides, Bacterial (administration & dosage)
  • Typhoid-Paratyphoid Vaccines (administration & dosage)
  • Urinary Bladder Neoplasms (immunology, therapy)

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