Immunosuppressive Role of Integrin β8 in Recurrence After Bacillus Calmette–Guérin (BCG) Therapy for Non-Muscle Invasive Bladder Cancer

<b>Background:</b> Although immunosuppressive factors contribute to the recurrence of non-muscle invasive bladder cancer (NMIBC) during Bacillus Calmette-Guérin (BCG) therapy, the mechanism remains unclear. <b>Methods:</b> In this study, key players in the immunosuppression associated with recurrence after BCG therapy were identified through comprehensive genetic and functional analyses of untreated NMIBC. <b>Results:</b> Microarray analysis of bladder cancer tissue from 13 eligible NMIBC patients revealed an association between high expression of <i>integrin β8</i> (<i>ITGB8</i>) and recurrence after BCG treatment (<i>p</i> < 0.001). In UMUC cells exhibiting high ITGB8 expression, <i>ITGB8</i> knockdown significantly decreased cell growth, invasion, adhesion, and secretion of the immunosuppressive cytokine transforming growth factor-β1 (TGF-β1, <i>p</i> < 0.01 for each). In addition, ITGB8 and TGF-β1 expression were correlated in immunohistochemistry of surgical specimens from 13 patients (<i>p</i> < 0.05). These results indicate that ITGB8 regulates TGF-β1 secretion. <b>Conclusions:</b> ITGB8 may contribute to post-BCG therapy recurrence of NMIBC by suppressing tumor immunity through the activation of TGF-β1. Evaluation of <i>ITGB8</i> expression in preoperative NMIBC could potentially predict recurrence following intravesical BCG therapy.