Roles for Androgen Receptor, ADAR2, and PD-L1 in Primary Urothelial Carcinoma In Situ of the Bladder Treated with...

In this retrospective observational multicenter study, we identified tumors and immune markers that are related to each other, which could help in selecting patients with bladder primary urothelial carcinoma in situ (CIS) who responded better to Bacillus Calmette-Guérin (BCG) therapy. Seventy-three patients with primary bladder CIS who were homogeneously treated with BCG were studied. Tumor-infiltrating lymphocytes (TILs) measured as CD4/CD8 ratio, androgen receptor (AR), adenosine deaminase acting on RNA 1 (ADAR1), adenosine deaminase acting on RNA 2 (ADAR2), and programmed death ligand 1 (PD-L1) expression were analyzed using immunohistochemistry, whereas miR-200a-3p and INF-γ were correlated with clinicopathological features and recurrence-free survival. High AR levels in CIS were significantly associated with higher ADAR1 expression, lower ADAR2 expression, higher PD-L1 TPS, higher CD4/CD8 ratio, and multifocality of CIS (P < .001). All patients with the above-mentioned characteristics had significantly worse recurrence-free survival (P < .0001). Multivariate and multiple regression analyses confirmed the predictive role of AR, ADAR2, and PD-L1, especially when all 3 parameters were combined. Additionally, we demonstrated that patients with lower AR and higher ADAR2 expressions had significantly higher levels of miR-200a-3p and INF-γ than those with higher AR and lower ADAR2 expression (P = .0011 and P = .0002, respectively). Our findings highlight the role of AR in the response to BCG therapy by modulating PD-L1 expression and TILs through the ADAR2, miR-200a-3p, and INF-γ pathways. Furthermore, our data provide valuable insights for optimizing BCG therapy in patients with CIS, paving the way for other possible combined treatment strategies.