Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer

Abstract

The cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)/B7 and programmed death 1 (PD-1)/ programmed cell death-ligand 1 (PD-L1) are two most representative immune checkpoint pathways, which negatively regulate T cell immune function during different phases of T-cell activation. Inhibitors targeting CTLA-4/B7 and PD1/PD-L1 pathways have revolutionized immunotherapies for numerous cancer types. Although the combined anti-CTLA-4/B7 and anti-PD1/PD-L1 therapy has demonstrated promising clinical efficacy, only a small percentage of patients receiving anti-CTLA-4/B7 or anti-PD1/PD-L1 therapy experienced prolonged survival. Regulation of the expression of PD-L1 and CTLA-4 significantly impacts the treatment effect. Understanding the in-depth mechanisms and interplays of PD-L1 and CTLA-4 could help identify patients with better immunotherapy responses and promote their clinical care. In this review, regulation of PD-L1 and CTLA-4 is discussed at the levels of DNA, RNA, and proteins, as well as indirect regulation of biomarkers, localization within the cell, and drugs. Specifically, some potential drugs have been developed to regulate PD-L1 and CTLA-4 expressions with high efficiency.

Keywords: CTLA-4; Cancer immunotherapy; Drug intervention; PD-L1; Regulatory mechanism.

Fig. 1

Overall regulatory mechanisms of PD-L1 and CTLA-4. TMB, tumor mutation burden; MSI, microsatellite instability; AP-1, adaptor protein 1; AP-2, adaptor protein 2.

Fig. 2

Regulatory mechanisms of PD-L1. PD-L1 expression is regulated at RNA level (inflammatory signaling, aberrant oncogenic signaling, regulation by miRNA, epigenetic regulation, mRNA stabilization), DNA level (genomic alteration, epigenetic regulation), and protein level (ubiquitination, phosphorylation, glycosylation, palmitoylation). Extracellular PD-L1 (exosome, soluble protein) and biomarkers also regulate PD-L1 expression.

Fig. 3

Regulatory mechanisms of CTLA-4. CTLA-4 expression is regulated at RNA level (transcriptional regulation, direct regulation by miRNA) and DNA level (epigenetic regulation). Localization within the cell also regulate CTLA-4 expression.

Fig. 4

Potential drug intervention on PD-L1 and CTLA-4.