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.
Oncoimmunology. 2023 Oct 19*** epublish ***
Niklas Klümper, Lennert Wüst, Jonas Saal, Damian J Ralser, Romina Zarbl, Jonas Jarczyk, Johannes Breyer, Danijel Sikic, Bernd Wullich, Christian Bolenz, Florian Roghmann, Michael Hölzel, Manuel Ritter, Sebastian Strieth, Arndt Hartmann, Philipp Erben, Ralph M Wirtz, Jennifer Landsberg, Dimo Dietrich, Markus Eckstein
Department of Urology and Pediatric Urology, University Medical Center Bonn (UKB), Bonn, Germany., Center for Integrated Oncology, Aachen/Bonn/Cologne/Düsseldorf (CIO-ABCD), Germany., Institute of Experimental Oncology, University Medical Center Bonn (UKB), Bonn, Germany., Department of Urology and Urosurgery, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany., Department of Urology, Caritas Hospital St. Josef, University of Regensburg, Regensburg, Germany., Center for Integrated Oncology, Bavarian Center for Cancer Research (Bayerisches Zentrum für Krebsforschung, BZKF), Erlangen, Germany., Department of Urology, University Hospital Ulm, Ulm, Germany., Department of Urology, Ruhr-University Bochum, Herne, Germany., Center for Integrated Oncology, STRATIFYER Molecular Pathology GmbH, Cologne, Germany.