The opportunities and challenges in immunotherapy: Insights from the regulation of PD-L1 in cancer cells

The immunosuppressive molecule programmed death-ligand 1 (PD-L1) is frequently upregulated in human cancers. Binding of PD-L1 to its receptor, programmed death-1 (PD-1), on activated T cells facilitates cancer cells to evade the host immune system. Antibody-based PD-1/PD-L1 inhibitors can inhibit PD-1/PD-L1 interaction allowing reactivate cytotoxic T cells to eradicate advanced cancer cells. However, the majority of cancer patients fail to respond to anti-PD-1/PD-L1 therapies and the molecular mechanisms for this remain poorly understood. Recent studies show that PD-L1 expression level on tumor cells affect the clinical efficacy of immune checkpoint therapies. Thus, furthering our understanding of the regulatory mechanisms of PD-L1 expression in cancer cells will be critical to improve clinical response rates and the efficacy of PD-1/PD-L1 immune therapies. Here we review recent studies, primarily focusing on the mechanisms that regulate PD-L1 expression at the transcriptional, post-transcriptional and protein level, with the purpose to drive the development of more targeted and effective anti-PD-1/PD-L1 cancer therapies.