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.