What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 5: Epigenetic Regulation of PD-L1

Abstract

Epigenetic alterations (including DNA methylation or miRNAs) influence oncogene/oncosuppressor gene expression without changing the DNA sequence. Prostate cancer (PC) displays a complex genetic and epigenetic regulation of cell-growth pathways and tumor progression. We performed a systematic literature review (following PRISMA guidelines) focused on the epigenetic regulation of PD-L1 expression in PC. In PC cell lines, CpG island methylation of the CD274 promoter negatively regulated PD-L1 expression. Histone modifiers also influence the PD-L1 transcription rate: the deletion or silencing of the histone modifiers MLL3/MML1 can positively regulate PD-L1 expression. Epigenetic drugs (EDs) may be promising in reprogramming tumor cells, reversing epigenetic modifications, and cancer immune evasion. EDs promoting a chromatin-inactive transcriptional state (such as bromodomain or p300/CBP inhibitors) downregulated PD-L1, while EDs favoring a chromatin-active state (i.e., histone deacetylase inhibitors) increased PD-L1 expression. miRNAs can regulate PD-L1 at a post-transcriptional level. miR-195/miR-16 were negatively associated with PD-L1 expression and positively correlated to longer biochemical recurrence-free survival; they also enhanced the radiotherapy efficacy in PC cell lines. miR-197 and miR-200a-c positively correlated to PD-L1 mRNA levels and inversely correlated to the methylation of PD-L1 promoter in a large series. miR-570, miR-34a and miR-513 may also be involved in epigenetic regulation.

Androgen receptor blockade resistance with enzalutamide in prostate cancer results in immunosuppressive alterations in the tumor immune microenvironment

“… 36 In prostate cancer, PD-L1 expression is regulated by the intracellular ERK/MEK, Akt-mTOR, NF-kB, WNT, and JAK/STAT pathways, as well as extracellular cytokines such as IFN-γ, IL-6, and TNF-α. 37 Additionally, epigenetic factors play a role in the regulation of PD-L1 expression. Studies have shown that acetylase p300/CBP can promote the recruitment of IRF-1 to the PD-L1 promoter and induce histone H3 acetylation, thereby promoting PD-L1 transcription and expression.…”

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review (Part 6): Correlation of PD-L1 Expression with the Status of Mismatch Repair System, BRCA, PTEN, and Other Genes

“…To better present the data of our SLR, we have split the discussion of our results into different articles, highlighting relevant subtopics: PD-L1 IHC expression in PC with discussion of pre-analytical and interpretation variables; correlations of PD-L1 expression with clinic–pathological features in PC patients; PD-L1 intracellular signaling pathways in PC cells and regulation of the tumor microenvironment; pre-clinical models (cell lines, mouse models) and experimental treatments affecting PD-L1 expression in PC cells; genetic and epigenetic regulation of PD-L1; PD-L1 expression in liquid biopsies, etc. [ 260 , 261 , 262 , 263 , 264 , 265 ].…”