Epigenetic regulators of programmed death-ligand 1 expression in human cancers

The programmed cell death protein 1-programmed death-ligand 1 (PD-L1) axis has been successfully targeted in clinics and the use of immune check-point inhibitors have shown durable antitumor response in untreated or heavily treated advanced stage cancer. PD-L1 upregulation has been found to correlate with poor prognosis in multiple cancer types and expression of PD-L1 in intratumoral compartment has been suggested to influence immune response and act as a key determinant of checkpoint immunotherapy efficacy. Hence it becomes critical to understand the regulation of PD-L1 expression in cancer. Role of oncogenic signaling pathways and transcription factors such as PI3K-AKT, MEK-ERK, JAK-STAT, MYC, HIF-1α, AP-1 and NF-κB is well established in inducing PD-L1 expression. Even the structural variations resulting in the truncation of the 3′ untranslated region (UTR) of PD-L1 has been shown to upregulate PD-L1 expression in multiple cancer types. Since microRNAs carry out post-transcriptional gene silencing by binding to the 3′ UTR of its target messenger RNA, truncation of PD-L1 3′ UTR can result in alleviation of PD-L1 suppression mediated by microRNA, leading to its overexpression. Other epigenetic modifications, such as promoter DNA methylation and histone modifications can also play crucial role in regulating PD-L1 expression. Here, we review recent findings and evidence on epigenetic mechanisms that regulate PD-L1 expression and the biological and clinical implications of such regulation in cancer.