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.

Automated summary

Programmed death-ligand 1 (PD-L1) is a frequently upregulated immunosuppressive molecule in human cancers. Antibody-based PD-1/PD-L1 inhibitors have shown potential in reactivating cytotoxic T cells to eliminate advanced cancer cells. However, the majority of cancer patients do not respond to these therapies, and the molecular mechanisms for this lack of response are poorly understood. Recent studies have highlighted the importance of PD-L1 expression levels on tumor cells in determining the efficacy of immune checkpoint therapies. Therefore, understanding the regulatory mechanisms of PD-L1 expression will be crucial for improving clinical response rates and the effectiveness of PD-1/PD-L1 immune therapies.