Mechanisms Controlling PD-L1 Expression in Cancer

Abstract

The engagement of programmed cell death protein 1 (PD-1; encoded by the PDCD1 gene) receptor expressed on activated T cells and its ligand, programmed death-ligand 1 (PD-L1; encoded by the CD274 gene), is a major co-inhibitory checkpoint signaling that controls T cell activities. Various types of cancers express high levels of PD-L1 and exploit PD-L1/PD-1 signaling to evade T cell immunity. Blocking the PD-L1/PD-1 pathway has consistently shown remarkable anti-tumor effects in patients with advanced cancers and is recognized as the gold standard for developing new immune checkpoint blockade (ICB) and combination therapies. However, the response rates of anti-PD-L1 have been limited in several solid tumors. Therefore, furthering our understanding of the regulatory mechanisms of PD-L1 can bring substantial benefits to patients with cancer by improving the efficacy of current PD-L1/PD-1 blockade or other ICBs. In this review, we provide current knowledge of PD-L1 regulatory mechanisms at the transcriptional, posttranscriptional, post-translational, and extracellular levels, and discuss the implications of these findings in cancer diagnosis and immunotherapy.

Figure 1.. The regulatory mechanism of PD-L1 expression.

The precise and complex regulation of PD-L1 expression includes genomic alteration, transcriptional regulation, post-transcriptional and post-translational modifications, and exosomal transport. Me: methylation, AC: acetylation

Figure 2.. Post-translational modifications (PTM) of PD-L1.

After translation, the activity and stability of PD-L1 are regulated by various PTM. Glycosylation and palmitoylation are essential to maintain the stability of PD-L1. In addition, glycosylation affects the binding between PD-L1 and PD-1. In contrast, poly-ubiquitination is a negative regulator that induces PD-L1 degradation. Phosphorylation regulates PD-L1 level through cross-talk with the glycosylation and poly-ubiquitination.