Current insight into the regulation of PD-L1 in cancer

Abstract

The molecular mechanisms underlying cancer immune escape are a core topic in cancer immunology research. Cancer cells can escape T cell-mediated cellular cytotoxicity by exploiting the inhibitory programmed cell-death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1, CD274) immune checkpoint. Studying the PD-L1 regulatory pattern of tumor cells will help elucidate the molecular mechanisms of tumor immune evasion and improve cancer treatment. Recent studies have found that tumor cells regulate PD-L1 at the transcriptional, post-transcriptional, and post-translational levels and influence the anti-tumor immune response by regulating PD-L1. In this review, we focus on the regulation of PD-L1 in cancer cells and summarize the underlying mechanisms.

Keywords: Cancer; Cancer immunotherapy; Epigenetic regulation; PD-L1; Post-translational modification; Transcriptional regulation.

Fig. 1

The expression and biological function of PD-L1. PD-L1 is expressed in hematopoietic cells, including T cells, B cells, DCs, macrophages, mast cells, and many non-hematopoietic cell types. PD-1 binds to PD-L1 to induce cancer cell immune escape, proliferation, drug resistance, and autophagy, and PD-1/PD-L1 blockade can inhibit these functions

Fig. 2

Overview of the regulatory mechanisms involved in PD-L1 expression. By attaching to the PD-L1 promoter, numerous transcription factors contribute to the increase of PD-L1 expression. N6-methyladenosine increases PD-L1 expression while DNA methylation, histone modification, and autophagy suppress it. MicroRNAs, including miR-138, miR-138-5p, miR-152, and others shown in Table 1, suppress PD-L1 by directly binding to the 3’UTR of PD-L1 mRNA. LncRNAs and circRNAs are also relevant to PD-L1 expression and tumor immune escape. PD-L1 is upregulated by glycosylation and palmitoylation, which stabilize PD-L1 protein, while ubiquitination, phosphorylation, and acetylation exert the opposite effect