| Item type: | Article | ||||
|---|---|---|---|---|---|
| Journal or Publication Title: | OncoImmunology | ||||
| Publisher: | TAYLOR & FRANCIS INC | ||||
| Place of Publication: | PHILADELPHIA | ||||
| Volume: | 12 | ||||
| Number of Issue or Book Chapter: | 1 | ||||
| Date: | 2023 | ||||
| Institutions: | Medicine > Lehrstuhl für Urologie | ||||
| Identification Number: |
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| 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 | ||||
| Dewey Decimal Classification: | 600 Technology > 610 Medical sciences Medicine | ||||
| Status: | Published | ||||
| Refereed: | Yes, this version has been refereed | ||||
| Created at the University of Regensburg: | Yes | ||||
| Item ID: | 76231 |
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 ...
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.
Metadata last modified: 18 Mar 2025 10:11
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