Posttranslational Modifications in PD-L1 Turnover and Function: From Cradle to Grave

Programmed death-ligand 1 (PD-L1) is one of the most classic immune checkpoint molecules. Cancer cells express PD-L1 to inhibit the activity of effector T cells’ cytotoxicity through programmed death 1 (PD-1) engagement in exposure to inflammatory cytokines. PD-L1 expression levels on cancer cells might affect the clinical response to anti-PD-1/PD-L1 therapies. Hence, understanding molecular mechanisms for regulating PD-L1 expression is essential for improving the clinical response rate and efficacy of PD-1/PD-L1 blockade. Posttranslational modifications (PTMs), including phosphorylation, glycosylation, ubiquitination, and acetylation, regulate PD-L1 stability, cellular translocation, and interaction with its receptor. A coordinated positive and negative regulation via PTMs is required to ensure the balance and function of the PD-L1 protein. In this review, we primarily focus on the roles of PTMs in PD-L1 expression, trafficking, and antitumor immune response. We also discuss the implication of PTMs in anti-PD-1/PD-L1 therapies.