PD-L1 degradation pathway and immunotherapy for cancer

Abstract

Programmed death ligand 1 (PD-L1, CD274) is an essential immune checkpoint protein that binds to programmed death 1 (PD-1) on T-lymphocytes. T cell plays a critical role in killing cancer cells while the cancer cell exhibits immune escape by the expression of PD-L1. The binding of PD-L1 to PD-1 inhibits T cell proliferation and activity, leading to tumor immunosuppression. Increasing evidence shows that PD-L1 protein undergoes degradation in proteasomes or lysosomes by multiple pathways, leading to enhanced immunotherapy for cancer. Although some specific drugs induce PD-L1 degradation and increase antitumor activity, the combination of these drugs with PD-L1/PD-1 blockade significantly enhances cancer immunotherapy. In this review, we have discussed the interaction of PD-L1 degradation with cancer immunotherapy.

Fig. 1. The pathways of PD-L1 ubiquitination and degradation.

PD-L1 undergoes ubiquitination and degradation by E3 ubiquitin ligases, including STUB1, Cullin3^SPOP, and β-TrCP, which is abolished by CMTM4/6, CSN5, and STT3. Although glycosylation of PD-L1 increases its protein stability, the AMPK agonist or EGFR inhibitor reverses this process and induces PD-L1 proteasome-dependent degradation. Moreover, in response to extracellular stimuli, PD-L1 protein triggers ubiquitination and degradation by multiple pathways.

Fig. 2. The pathways of PD-L1 autophagic degradation.

HIP1R, PKCα/GSK3β/MITF, ADAM10/17, and endosomal sorting-signal induce PD-L1 protein degradation by autophagy, which is inhibited by CMTM6, DHHC3, and Sigma I. In response to extracellular stimuli or specific anti-PD-L1 antibody such as HA or STM108, PD-L1 protein is degraded via autophagy.