Mechanisms regulating PD-L1 expression in cancers and associated opportunities for novel small-molecule therapeutics

• Published in: Nature reviews. Clinical oncology Vol. 19; no. 5; pp. 287 - 305
• Main Authors: Yamaguchi, Hirohito, Hsu, Jung-Mao, Yang, Wen-Hao, Hung, Mien-Chie
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2022; Nature Publishing Group
• Subjects: 692/308/153; 692/308/575; 692/699/67/580; 692/700/565/251; Acetylation; Antibodies; B7-H1 Antigen; Cancer; Drug development; Gene regulation; Glycosylation; Humans; Immune checkpoint inhibitors; Immunosuppressive agents; Ligands; Medicine; Medicine & Public Health; Molecular Targeted Therapy; Neoplasms - drug therapy; Neoplasms - genetics; Oncology; Palmitoylation; Patients; PD-1 protein; PD-L1 protein; Phosphorylation; Post-transcription; Post-translation; Programmed Cell Death 1 Receptor; Review Article; Signal Transduction; Synergism; Translation; Ubiquitination
• ISSN: 1759-4774; 1759-4782
• DOI: 10.1038/s41571-022-00601-9

Antagonistic antibodies targeting the inhibitory immune-checkpoint receptor PD-1 or its ligand PD-L1 are used to treat a wide range of cancer types and can substantially improve patient survival. Nevertheless, strategies to overcome intrinsic and acquired resistance are required to respectively increase response rates and durations. PD-L1 is often upregulated in various malignancies, and emerging evidence suggests numerous underlying mechanisms involving distinct oncogenic signalling pathways. Thus, specific small-molecule inhibitors have the potential to simultaneously suppress not only a key oncogenic signalling pathway but also PD-L1 expression and/or activity in particular cancers, thereby presenting attractive candidate drugs for combination with existing immune-checkpoint inhibitors and/or other targeted agents. Herein, we summarize advances in understanding the mechanisms regulating PD-L1 expression at the transcriptional, post-transcriptional, translational and post-translational levels in cancers. We describe the roles of the diverse post-translational modifications of PD-L1, including phosphorylation, palmitoylation, glycosylation, acetylation and ubiquitination. Moreover, we discuss the potential use of small-molecule agents to modulate these mechanisms as well as of predictive biomarkers to stratify patients for optimal treatment, and provide our perspective on potential therapeutic strategies to circumvent resistance to conventional anti-PD-1/PD-L1 antibodies. Antibodies targeting PD-1 or its ligand PD-L1 have revolutionized cancer therapy. Increased understanding of the mechanisms regulating PD-L1 has revealed links with several important oncogenic signalling pathways. Herein, the authors review the transcriptional, post-transcriptional and translational regulation of PD-L1 expression in cancers as well as the diverse post-translational modifications, including phosphorylation, palmitoylation, glycosylation, acetylation and ubiquitination, that affect PD-L1 stability and activity. They also discuss the possibility to simultaneously target key oncogenic pathways and modulate PD-L1 expression using small-molecule agents, which have potential advantages over or might synergize with anti-PD-1/PD-L1 antibodies. Key points Besides its localization on the cell membrane, PD-L1 can also be detected in the extracellular space or nucleus, where it has crucial roles in regulating immune evasion and tumorigenesis through PD-1-dependent or PD-1-independent activities. Transcriptional, post-transcriptional and translational mechanisms contribute to PD-L1 overexpression in cancers, and these mechanisms are regulated by diverse oncogenic signalling and stress response pathways. In addition, PD-L1 expression and/or activity is regulated through several post-translational modifications, including phosphorylation, glycosylation, acetylation, ubiquitination and palmitoylation, which serve as signals for lysosomal or proteasome-mediated degradation of PD-L1. Small-molecule agents that either upregulate or downregulate PD-L1 expression have been extensively investigated in preclinical studies and for different purposes in clinical trials; most of these agents have the potential to both inhibit oncogenic signalling pathways and modulate PD-L1 expression. Rational combinations of such small-molecule agents and conventional, antibody-based immune-checkpoint inhibitors might improve efficacy over that of either agent as monotherapy and/or overcome resistance mechanisms.