PD-L1 (CD274) promoter hypomethylation predicts immunotherapy response in metastatic urothelial carcinoma
Klümper N, Wüst L, Saal J, Ralser DJ, Zarbl R, Jarczyk J, Breyer J, Sikic D, Wullich B, Bolenz C, Roghmann F, Hölzel M, Ritter M, Strieth S, Hartmann A, Erben P, Wirtz RM, Landsberg J, Dietrich D, Eckstein M (2023)
Publication Type: Journal article
Publication year: 2023
Journal
Book Volume: 12
Article Number: 2267744
Journal Issue: 1
DOI: 10.1080/2162402X.2023.2267744
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-γ 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 γ. Hypomethylation of the PD-L1 promoter is a promising predictive biomarker for response to ICB in patients with mUC.
Involved external institutions
Universitätsklinikum Bonn
Germany (DE)
Centrum für Integrierte Onkologie Aachen Bonn Köln Düsseldorf (CIO ABCD)
Germany (DE)
Universitätsklinikum Mannheim
Germany (DE)
Universität Regensburg
Germany (DE)
Bayerisches Zentrum für Krebsforschung (BZKF)
Germany (DE)
Universitätsklinikum Ulm
Germany (DE)
Ruhr-Universität Bochum (RUB)
Germany (DE)
Germany (DE)
Centrum für Integrierte Onkologie Aachen Bonn Köln Düsseldorf (CIO ABCD)
Germany (DE)
Universitätsklinikum Mannheim
Germany (DE)
Universität Regensburg
Germany (DE)
Bayerisches Zentrum für Krebsforschung (BZKF)
Germany (DE)
Universitätsklinikum Ulm
Germany (DE)
Ruhr-Universität Bochum (RUB)
Germany (DE)
How to cite
APA:
Klümper, N., Wüst, L., Saal, J., Ralser, D.J., Zarbl, R., Jarczyk, J.,... Eckstein, M. (2023). PD-L1 (CD274) promoter hypomethylation predicts immunotherapy response in metastatic urothelial carcinoma. OncoImmunology, 12(1). https://doi.org/10.1080/2162402X.2023.2267744
MLA:
Klümper, Niklas, et al. "PD-L1 (CD274) promoter hypomethylation predicts immunotherapy response in metastatic urothelial carcinoma." OncoImmunology 12.1 (2023).
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