PD-L1promoter methylation is a prognostic biomarker for biochemical recurrence-free survival in prostate cancer patients following radical prostatectomy

// Heidrun Gevensleben 1, * , Emily Eva Holmes 1, * , Diane Goltz 1, * , Jörn Dietrich 2 , Verena Sailer 3, 4 , Jörg Ellinger 5 , Dimo Dietrich 1, 2, ** , Glen Kristiansen 1, ** 1 Institute of Pathology, University Hospital Bonn, Bonn, Germany 2 Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Bonn, Germany 3 Weill Cornell Medicine of Cornell University, Department of Pathology and Laboratory Medicine, New York, NY, USA 4 Weill Cornell Medicine of Cornell University, Englander Institute for Precision Medicine, New York, NY, USA 5 Department of Urology, University Hospital Bonn, Bonn, Germany * These authors have contributed equally to this work ** These authors are joint senior authors of this work Correspondence to: Dimo Dietrich, email: dimo.dietrich@gmail.com Keywords: PD-L1, prostate cancer, DNA methylation, prognostic biomarker Received: August 05, 2016     Accepted: October 13, 2016     Published: November 07, 2016 ABSTRACT Background: The rapid development of programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors has generated an urgent need for biomarkers assisting the selection of patients eligible for therapy. The use of PD-L1 immunohistochemistry, which has been suggested as a predictive biomarker, however, is confounded by multiple unresolved issues. The aim of this study therefore was to quantify PD-L1 DNA methylation ( mPD-L1 ) in prostate tissue samples and to evaluate its potential as a biomarker in prostate cancer (PCa). Results: In the training cohort, normal tissue showed significantly lower levels of mPD-L1 compared to tumor tissue. High mPD-L1 in PCa was associated with biochemical recurrence (BCR) in univariate Cox proportional hazards (hazard ratio (HR)=2.60 [95%CI: 1.50-4.51], p=0.001) and Kaplan-Meier analyses (p<0.001). These results were corroborated in an independent validation cohort in univariate Cox (HR=1.24 [95%CI: 1.08-1.43], p=0.002) and Kaplan-Meier analyses (p=0.029). Although mPD-L1 and PD-L1 protein expression did not correlate in the validation cohort, both parameters added significant prognostic information in bivariate Cox analysis (HR=1.22 [95%CI: 1.05-1.42], p=0.008 for mPD-L1 and HR=2.58 [95%CI: 1.43-4.63], p=0.002 for PD-L1 protein expression). Methods: mPD-L1 was analyzed in a training cohort from The Cancer Genome Atlas (n=498) and was subsequently measured in an independent validation cohort (n=299) by quantitative methylation-specific real-time PCR. All patients had undergone radical prostatectomy. Conclusions: mPD-L1 is a promising biomarker for the risk stratification of PCa patients and might offer additional relevant prognostic information to the implemented clinical parameters, particularly in the setting of immune checkpoint inhibition.