Abstract
Simple SummaryAdvanced urothelial bladder cancer (BC) shows a heterogeneous response to both platinum and immune checkpoint inhibitor (ICI) therapies. The PD-1/PD-L1 signaling pathway represents an immune escape mechanism and tissue PD-L1 expression was shown to be associated with patients’ prognosis and therapy response in various solid tumors. In the present study, we found for the first time that higher pretreatment serum PD-L1 levels are associated with shorter survival in platinum- and ICI-treated BC patients.Serum PD-L1 (sPD-L1) levels are associated with prognosis in various tumors but has not yet been investigated in advanced bladder cancer. We assessed pretreatment serum samples from 83 BC patients who received platinum chemotherapy and from 12 patients who underwent immune checkpoint inhibitor (ICI) therapy. In addition, on-treatment samples from further therapy cycles were collected during chemotherapy (n = 58) and ICI therapy (n = 11). Serum PD-L1 levels were determined using ELISA. High baseline sPD-L1 levels were associated with worse ECOG status (p = 0.007) and shorter overall survival for both chemotherapy- and ICI-treated patients (p = 0.002 and p = 0.040, respectively). Multivariate analysis revealed high baseline sPD-L1 level as an independent predictor of poor survival for platinum-treated patients (p = 0.002). A correlation analysis between serum concentrations of PD-L1 and matrix metalloprotease-7 (MMP-7)—a protease which was recently found to cleave PD-L1—revealed a positive correlation (p = 0.001). No significant sPD-L1 changes were detected during chemotherapy, while in contrast we found a strong, 25-fold increase in sPD-L1 levels during atezolizumab treatment. In conclusion, our work demonstrates that pretreatment sPD-L1 levels are associated with a poor prognosis of BC patients undergoing platinum and ICI therapy. Future research should prospectively address the value of sPD-L1 in predicting treatment response.
Highlights
Urothelial bladder cancer is the most common malignancy of the urinary tract and represents one of the most frequently diagnosed cancers in western countries [1]
A published dataset with available pre- and post-treatment PD-L1 expression in patients who received neoadjuvant atezolizumab therapy revealed a moderate but significant increase in PD-L1 expression in the post-treatment tissues, this increase was much lower compared to that we found in the serum samples and we suppose that bladder cancer cells may not be the primary source of the increased post-treatment serum PD-L1 flare-up [33]
We demonstrated, that pretreatment serum PD-L1 is independently associated with poor survival of platinum-treated bladder cancer patients
Summary
Urothelial bladder cancer is the most common malignancy of the urinary tract and represents one of the most frequently diagnosed cancers in western countries [1]. Bladder cancers are clinically classified into non-muscle-invasive (NMIBC) and muscle-invasive bladder cancer (MIBC), with distinct implications for patient management. Radical cystectomy (RC) is the standard treatment for patients with MIBC. 5-year survival in about 50% of patients [2]. To improve these results, cisplatin-based neoadjuvant chemotherapy (NAC) is recommended to eligible patients [3]. Only less than 20% of all patients receive NAC before RC [4]. Adjuvant platinum-based chemotherapy is administered after RC for T3/4 and/or lymph node metastatic tumors when no neoadjuvant treatment was applied. First-line platinum therapy for metastatic disease provides a median survival of ~15 months and a 5-year overall survival rate of
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