Emerging Role of Ubiquitination in the Regulation of PD-1/PD-L1 in Cancer Immunotherapy

Abstract

A growing amount of evidence suggests that ubiquitination and deubiquitination of programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) play crucial roles in the regulation of PD-1 and PD-L1 protein stabilization and dynamics. PD-1/PD-L1 is a major coinhibitory checkpoint pathway that modulates immune escape in cancer patients, and its engagement and inhibition has significantly reshaped the landscape of tumor clearance. The abnormal ubiquitination and deubiquitination of PD-1/PD-L1 influence PD-1/PD-L1-mediated immunosuppression. In this review, we describe the ubiquitination- and deubiquitination-mediated modulation of PD-1/PD-L1 signaling through a variety of E3 ligases and deubiquitinating enzymes (DUBs). Moreover, we briefly expound on the anticancer potential of some agents that target related E3 ligases, which further modulate the ubiquitination of PD-1/PD-L1 in cancers. Therefore, this review reveals the development of a highly promising therapeutic approach for cancer immunotherapy by targeting PD-1/PD-L1 ubiquitination.

Keywords: PD-1; PD-L1; deubiquitination; immunotherapy; ubiquitination.

Graphical abstract

Figure 1

The Ubiquitination and Deubiquitination Processes Are Illustrated The ubiquitin-proteasome system is composed of ubiquitin, ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin-protein enzymes (E3s), deubiquitinating enzymes (DUBs), and the 26S proteasome. Ubiquitination has a series of enzyme-linked reactions mediated by E1, E2, and E3 ligases. The carboxyl group (-COOH) of the C terminus of ubiquitin binds to an E1 cysteine residue along with ATP and is thus stimulated by a thioester link with E1. The E2 ligase temporarily transfers ubiquitin moieties with a thioester linkage. Activated ubiquitin is moved from E2 to the lysine residue on substrates by E3. Ubiquitination is controlled by E3 ligases, whose activities can be reversed by DUBs. Ubiquitination and deubiquitination play a crucial role in the regulation of PD-1/PD-L1 in cancer.

Figure 2

Ubiquitination-Mediated Regulation of PD-L1 Signaling Is Presented The several E3 ligases, including SPOP, HRD1, Cbl-b, c-Cbl, STUB1, DCUND1, and β-TrCP, participate in PD-L1 ubiquitination. USP22, USP9X, and CSN5 are involved in PD-L1 deubiquitination in carcinoma.