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PD-L1 (CD274) promoter hypomethylation predicts immunotherapy response in metastatic urothelial carcinoma

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 vari...

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Autores principales: Klümper, Niklas, Wüst, Lennert, Saal, Jonas, Ralser, Damian J., Zarbl, Romina, Jarczyk, Jonas, Breyer, Johannes, Sikic, Danijel, Wullich, Bernd, Bolenz, Christian, Roghmann, Florian, Hölzel, Michael, Ritter, Manuel, Strieth, Sebastian, Hartmann, Arndt, Erben, Philipp, Wirtz, Ralph M., Landsberg, Jennifer, Dietrich, Dimo, Eckstein, Markus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10588513/
https://www.ncbi.nlm.nih.gov/pubmed/37868689
http://dx.doi.org/10.1080/2162402X.2023.2267744
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author Klümper, Niklas
Wüst, Lennert
Saal, Jonas
Ralser, Damian J.
Zarbl, Romina
Jarczyk, Jonas
Breyer, Johannes
Sikic, Danijel
Wullich, Bernd
Bolenz, Christian
Roghmann, Florian
Hölzel, Michael
Ritter, Manuel
Strieth, Sebastian
Hartmann, Arndt
Erben, Philipp
Wirtz, Ralph M.
Landsberg, Jennifer
Dietrich, Dimo
Eckstein, Markus
author_facet Klümper, Niklas
Wüst, Lennert
Saal, Jonas
Ralser, Damian J.
Zarbl, Romina
Jarczyk, Jonas
Breyer, Johannes
Sikic, Danijel
Wullich, Bernd
Bolenz, Christian
Roghmann, Florian
Hölzel, Michael
Ritter, Manuel
Strieth, Sebastian
Hartmann, Arndt
Erben, Philipp
Wirtz, Ralph M.
Landsberg, Jennifer
Dietrich, Dimo
Eckstein, Markus
author_sort Klümper, Niklas
collection PubMed
description 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.
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spelling pubmed-105885132023-10-21 PD-L1 (CD274) promoter hypomethylation predicts immunotherapy response in metastatic urothelial carcinoma Klümper, Niklas Wüst, Lennert Saal, Jonas Ralser, Damian J. Zarbl, Romina Jarczyk, Jonas Breyer, Johannes Sikic, Danijel Wullich, Bernd Bolenz, Christian Roghmann, Florian Hölzel, Michael Ritter, Manuel Strieth, Sebastian Hartmann, Arndt Erben, Philipp Wirtz, Ralph M. Landsberg, Jennifer Dietrich, Dimo Eckstein, Markus Oncoimmunology Original Research 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. Taylor & Francis 2023-10-19 /pmc/articles/PMC10588513/ /pubmed/37868689 http://dx.doi.org/10.1080/2162402X.2023.2267744 Text en © 2023 The Author(s). Published with license by Taylor & Francis Group, LLC. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
spellingShingle Original Research
Klümper, Niklas
Wüst, Lennert
Saal, Jonas
Ralser, Damian J.
Zarbl, Romina
Jarczyk, Jonas
Breyer, Johannes
Sikic, Danijel
Wullich, Bernd
Bolenz, Christian
Roghmann, Florian
Hölzel, Michael
Ritter, Manuel
Strieth, Sebastian
Hartmann, Arndt
Erben, Philipp
Wirtz, Ralph M.
Landsberg, Jennifer
Dietrich, Dimo
Eckstein, Markus
PD-L1 (CD274) promoter hypomethylation predicts immunotherapy response in metastatic urothelial carcinoma
title PD-L1 (CD274) promoter hypomethylation predicts immunotherapy response in metastatic urothelial carcinoma
title_full PD-L1 (CD274) promoter hypomethylation predicts immunotherapy response in metastatic urothelial carcinoma
title_fullStr PD-L1 (CD274) promoter hypomethylation predicts immunotherapy response in metastatic urothelial carcinoma
title_full_unstemmed PD-L1 (CD274) promoter hypomethylation predicts immunotherapy response in metastatic urothelial carcinoma
title_short PD-L1 (CD274) promoter hypomethylation predicts immunotherapy response in metastatic urothelial carcinoma
title_sort pd-l1 (cd274) promoter hypomethylation predicts immunotherapy response in metastatic urothelial carcinoma
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10588513/
https://www.ncbi.nlm.nih.gov/pubmed/37868689
http://dx.doi.org/10.1080/2162402X.2023.2267744
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