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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Taylor & Francis Group
2023-12-01
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| Series: | OncoImmunology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2023.2267744 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Niklas Klümper |
| collection | DOAJ |
| 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. |
| format | Article |
| id | doaj-art-db84a83835784401bcaeca4a8df3487d |
| institution | OA Journals |
| issn | 2162-402X |
| language | English |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj-art-db84a83835784401bcaeca4a8df3487d2025-08-20T02:01:29ZengTaylor & Francis GroupOncoImmunology2162-402X2023-12-0112110.1080/2162402X.2023.2267744PD-L1 (CD274) promoter hypomethylation predicts immunotherapy response in metastatic urothelial carcinomaNiklas Klümper0Lennert Wüst1Jonas Saal2Damian J. Ralser3Romina Zarbl4Jonas Jarczyk5Johannes Breyer6Danijel Sikic7Bernd Wullich8Christian Bolenz9Florian Roghmann10Michael Hölzel11Manuel Ritter12Sebastian Strieth13Arndt Hartmann14Philipp Erben15Ralph M. Wirtz16Jennifer Landsberg17Dimo Dietrich18Markus Eckstein19Department of Urology and Pediatric Urology, University Medical Center Bonn (UKB), Bonn, GermanyCenter for Integrated Oncology, Aachen/Bonn/Cologne/Düsseldorf (CIO-ABCD), GermanyCenter for Integrated Oncology, Aachen/Bonn/Cologne/Düsseldorf (CIO-ABCD), GermanyInstitute of Experimental Oncology, University Medical Center Bonn (UKB), Bonn, GermanyCenter for Integrated Oncology, Aachen/Bonn/Cologne/Düsseldorf (CIO-ABCD), GermanyDepartment of Urology and Urosurgery, Medical Faculty Mannheim, University of Heidelberg, Mannheim, GermanyDepartment of Urology, Caritas Hospital St. Josef, University of Regensburg, Regensburg, GermanyCenter for Integrated Oncology, Bavarian Center for Cancer Research (Bayerisches Zentrum für Krebsforschung, BZKF), Erlangen, GermanyCenter for Integrated Oncology, Bavarian Center for Cancer Research (Bayerisches Zentrum für Krebsforschung, BZKF), Erlangen, GermanyDepartment of Urology, University Hospital Ulm, Ulm, GermanyDepartment of Urology, Ruhr-University Bochum, Herne, GermanyInstitute of Experimental Oncology, University Medical Center Bonn (UKB), Bonn, GermanyDepartment of Urology and Pediatric Urology, University Medical Center Bonn (UKB), Bonn, GermanyCenter for Integrated Oncology, Aachen/Bonn/Cologne/Düsseldorf (CIO-ABCD), GermanyCenter for Integrated Oncology, Bavarian Center for Cancer Research (Bayerisches Zentrum für Krebsforschung, BZKF), Erlangen, GermanyDepartment of Urology and Urosurgery, Medical Faculty Mannheim, University of Heidelberg, Mannheim, GermanyCenter for Integrated Oncology, STRATIFYER Molecular Pathology GmbH, Cologne, GermanyCenter for Integrated Oncology, Aachen/Bonn/Cologne/Düsseldorf (CIO-ABCD), GermanyCenter for Integrated Oncology, Aachen/Bonn/Cologne/Düsseldorf (CIO-ABCD), GermanyCenter for Integrated Oncology, Bavarian Center for Cancer Research (Bayerisches Zentrum für Krebsforschung, BZKF), Erlangen, GermanyPD-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.https://www.tandfonline.com/doi/10.1080/2162402X.2023.2267744biomarkerbladder cancerCD274DNA methylationimmune checkpoint blockadeimmunotherapy |
| spellingShingle | 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 PD-L1 (CD274) promoter hypomethylation predicts immunotherapy response in metastatic urothelial carcinoma OncoImmunology biomarker bladder cancer CD274 DNA methylation immune checkpoint blockade immunotherapy |
| 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 | biomarker bladder cancer CD274 DNA methylation immune checkpoint blockade immunotherapy |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2023.2267744 |
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