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

Abstract

BackgroundThe 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).ResultsIn 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).MethodsmPD-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.ConclusionsmPD-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.

Decitabine Augments Chemotherapy-Induced PD-L1 Upregulation for PD-L1 Blockade in Colorectal Cancer

“…Previous studies have indicated that the DNA methylation of the PD-L1 promoter is associated with PD-L1 expression [22,23]. Therefore, we aimed to evaluate the effect of DNA methyltransferase (DNMT) inhibitors 5 -azacitidine (5-AC) and SGI-1027 (SGI) on PD-L1 expression.…”

“…Our previous studies indicated a strong correlation between tumor PD-L1 expression and CD8+ tumor-infiltrating lymphocytes (TILs), possibly due to the concomitant increase in interferon γ (IFNγ) expression by CD8+ T cells, and the PD-L1 level is positively correlated with favorable prognosis in CRC patients [10,21]. Additionally, the methylation of the PD-L1 promoter has been shown to negative correlate with its gene expression and is clinically associated with survival, including from prostate cancer, colorectal cancer, acute myeloid leukemia and melanoma [22][23][24][25]. However, the mechanism of the epigenetic regulation of PD-L1 is poorly defined.…”

PD-L1 (CD274) promoter methylation predicts survival in colorectal cancer patients

“…11 In prostate cancer and acute myeloid leukemia cohorts analyzed by The Cancer Genome Atlas (TCGA), CD274 promoter methylation (mPD-L1) correlates with gene expression and is associated with survival. 12,13 We therefore hypothesized that PD-L1 expression might be under direct epigenetic control in CRC as well and consequently might be of major importance for the stratification of patients potentially benefitting from immunotherapeutic PD-1/PD-L1 checkpoint inhibition.…”

Specific zinc finger‐induced methylation of PD‐L1 promoter inhibits its expression

“…The specific roles of these Dnmts in de novo and maintenance functions have recently been re‐examined. Although single knockout of either Dnmt1 or Dnmt3b gene had minimal effects on DNA demethylation in colon cancer cells, knockouts of both Dnmt1 and Dnmt3b genes led to demethylation and re‐expression of tumor suppressor genes in these cells . This observation implies that Dnmt1 and Dnmt3b together cooperate to maintain DNA methylation patterns and to silence genes in human cancer cells.…”