Kluemper, Niklas and Wuest, Lennert and Saal, Jonas and Ralser, Damian J. and Zarbl, Romina and Jarczyk, Jonas and Breyer, Johannes and Sikic, Danijel and Wullich, Bernd and Bolenz, Christian and Roghmann, Florian and Hoelzel, Michael and Ritter, Manuel and Strieth, Sebastian and Hartmann, Arndt and Erben, Philipp and Wirtz, Ralph M. and Landsberg, Jennifer and Dietrich, Dimo and Eckstein, Markus (2023) PD-L1 (CD274) promoter hypomethylation predicts immunotherapy response in metastatic urothelial carcinoma. ONCOIMMUNOLOGY, 12 (1): 2267744. ISSN 2162-402X,
Full text not available from this repository. (Request a copy)Abstract
PD-L1 status assessed by immunohistochemistry (IHC) has failed to reliably predict outcomes for patients with metastatic urothelial carcinoma (mUC) on immune checkpoint blockade (ICB). PD-L1 promoter methylation is an epigenetic mechanism that has been shown to regulate PD-L1 mRNA expression in various malignancies. The aim of our present study was to evaluate the predictive potential of PD-L1 promoter methylation status (mPD-L1) in ICB-treated mUC compared to conventional IHC-based PD-L1 assessment. We quantified mPD-L1 in formalin-fixed and paraffin-embedded tissue sections using an established quantitative methylation-specific PCR assay (qMSP) in a well-characterized multicenter ICB-treated cohort comprising N = 107 patients with mUC. Additionally, PD-L1 protein expression in tumor tissues was assessed using regulatory approved IHC protocols. The effect of pharmacological hypomethylation by the DNA methyltransferase inhibitor decitabine in combination with interferon-gamma stimulation in urothelial carcinoma cell lines was investigated by IHC and FACS. mPD-L1 hypomethylation predicted objective response rate at the first staging on ICB. Patients with tumors categorized as PD-L1 hypomethylated (lower quartile) showed significantly prolonged progression-free (PFS) and overall survival (OS) after ICB initiation. In contrast, PD-L1 protein expression status neither correlated with response nor survival. In multivariable Cox regression analyses, PD-L1 promoter hypermethylation remained an independent predictor of unfavorable PFS and OS. In urothelial carcinoma cell lines, pharmacological demethylation led to an upregulation of membranous PD-L1 expression and an enhanced inducibility of PD-L1 expression by interferon gamma. Hypomethylation of the PD-L1 promoter is a promising predictive biomarker for response to ICB in patients with mUC.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CISPLATIN-INELIGIBLE PATIENTS; DNA METHYLATION; T-CELLS; PROSTATE-CANCER; SINGLE-ARM; BIOMARKERS; PEMBROLIZUMAB; ATEZOLIZUMAB; MULTICENTER; KEYNOTE-052; biomarker; bladder cancer; CD274; DNA methylation; immune checkpoint blockade; immunotherapy; metastatic urothelial carcinoma; PD-L1; promoter methylation |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Urologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 18 Apr 2024 13:52 |
| Last Modified: | 18 Apr 2024 13:52 |
| URI: | https://pred.uni-regensburg.de/id/eprint/60859 |
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