Data Sheet 1_Characterization of Ty21a immunostimulatory effects in the mouse bladder.pdf
<p>Intravesical treatment with Salmonella enterica Ty21a, an oral typhoid-fever vaccine, has shown therapeutic potential against bladder tumors mainly through local immune-cell recruitment, particularly CD8<sup>+</sup> T-cells. However, the mechanisms underlying its efficacy and th...
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2025
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| Sumari: | <p>Intravesical treatment with Salmonella enterica Ty21a, an oral typhoid-fever vaccine, has shown therapeutic potential against bladder tumors mainly through local immune-cell recruitment, particularly CD8<sup>+</sup> T-cells. However, the mechanisms underlying its efficacy and the impact of bacterial formulation remain unclear. Here, we show that increased immune-cell infiltration was neither associated with modification in blood vessel density nor the generation of high endothelial venules, but rather with a transient increase in local vessel permeability, requiring live bacteria. Giving prior evidence that freshly harvested bacteria (Ty21a<sup>FR</sup>) were more efficient than lyophilized bacteria (Ty21a<sup>LYO</sup>), we tested both formulations intravesically in mice. Although, both similarly increased vascular permeability, Ty21a<sup>FR</sup> induced significantly greater immune-cell recruitment locally and more effective tumor regression in the orthotopic MB49 bladder cancer model. Chemokine analysis showed higher levels of C5a, CXCL2 and CXCL5 in Ty21a<sup>FR</sup>-treated bladders, however their receptors (C5aR, CXCR2) were barely detected on infiltrating T cells, precluding their direct involvement in T-cell recruitment. Instead, Ty21a<sup>FR</sup> increased C5aR<sup>+</sup> and C5aR<sup>-</sup>CD11b<sup>high</sup> myeloid cells, suggesting their indirect influence on T-cell recruitment. We hypothesized that LPS, a TLR4 agonist, from Salmonella, might be involved. Indeed, CD8<sup>+</sup> T-cell infiltration following Ty21a<sup>FR</sup> was significantly decreased in TLR4- and MyD88-KO mice. In contrast, myeloid-cell recruitment was only reduced in MyD88-KO mice, suggesting the involvement of TLR4-independent pathways in that process. This study is the first to identify Ty21a formulation-driven immunostimulatory differences in bladder cancer. Altogether, our data provide new insights into Ty21a’s immunostimulatory mechanisms and highlight the importance of bacterial formulation for optimizing bladder cancer treatment.</p> |
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