Intravesical Ty21a vaccine promotes dendritic cells and T cell-mediated tumor regression in the MB49 bladder cancer model

Preclinical data shows 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 nonmuscle-invasive bladder cancer (NMIBC). Here we characterized the inflammatory effects of Ty21a on the bladder and investigated the immune mechanisms underlying tumor-regression towards 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 immunohistochemistry 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 Ty21a bladder tumor responses. Thus, the generation of antitumor adaptive immunity was identified as a key process underlying Ty21a-mediated treatment efficacy. Altogether, these results demonstrate mechanisms of intravesical Ty21a therapy and suggest its potential as a safe and effective treatment for NMIBC patients.