Post-translational Modification of PD-1: Potential Targets for Cancer Immunotherapy

Abstract

Activation of effector T cells leads to upregulation of PD-1, which can inhibit T-cell activity following engagement with its ligand PD-L1. Post-translational modifications (PTM), including glycosylation, phosphorylation, ubiquitination, and palmitoylation, play a significant role in regulating PD-1 protein stability, localization, and interprotein interactions. Targeting PTM of PD-1 in T cells has emerged as a potential strategy to overcome PD-1-mediated immunosuppression in cancer and enhances antitumor immunity. The regulatory signaling pathways that induce PTM of PD-1 can be suppressed with small-molecule inhibitors, and mAbs can directly target PD-1 PTMs. Preliminary outcomes from exploratory studies suggest that focusing on the PTM of PD-1 has strong therapeutic potential and can enhance the response to anti-PD-1.

Figure 1.

Summary of PD-1 PTMs. Top, PD-1 domains with different sites of PTMs are illustrated. Bottom, the table summarizes the characterizations of five PTMs found on PD-1, including glycosylation, fucosylation, phosphorylation, palmitoylation, and ubiquitination. B3GNT2, β-1,3-N-acetylglucosaminyltransferase 2; c-Cbl, casitas B-lineage lymphoma; CDK1, cyclin-dependent kinase 1; DHHC9, aspartate-histidine-histidine-cysteine acyltransferases 9; FBW7, F-box and WD repeat domain containing 7; FBXO38, F-box only protein 38; FUT8, fucosyltransferase 8; ITIM, immunoreceptor tyrosine-based inhibitory motif; ITSM, immunoreceptor tyrosine-based switch motif; KLHL22, Kelch-like family member 22; MDM2, mouse double minute 2; SHP2, Src homology-2 domain-containing protein tyrosine phosphatase-2; USP5, ubiquitin specific peptidase 5.

Figure 2.

Schematic of PD-1 polyubiquitination and deubiquitination. Regulation of PD-1 ubiquitination by E3 ligases, including FBXO38, FBW7, KLHL22, and c-Cbl. Destabilization of PD-1 by IL2 inducing FBXO38-mediated PD-1 ubiquitination (left), whereas EOA13402143 inhibits deubiquitinating enzyme USP5 to degrade PD-1 for immune activation (right). (Created with BioRender.com.)