Abstract
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.
Highlights
Section of Epidemiology and Population Science, Department of Medicine, Baylor College of Medicine, Hematopathology Division, Department of Pathology, Duke University Medical Center, Abstract: Programmed death-ligand 1 (PD-L1) is one of the most classic immune checkpoint molecules
Monoclonal antibodies against programmed death 1 (PD-1) or its ligand, programmed death-ligand 1 (PD-L1) [2], have opened a new era for cancer therapy [3,4,5,6,7]
Most protein synthesis and Posttranslational modifications (PTMs) occur in the cytosol, where a complex system of targeting, sorting, recycling, and consigning is in place
Summary
Immunotherapies such as T cell adoptive transfer, mRNA vaccines, and checkpoint inhibitors are effective cancer treatment strategies [1]. PTMs include phosphorylation, glycosylation, ubiquitination, methylation, and acetylation, playing essential roles in regulating protein activity, Academic Editor: David T. PD-L1 may be transported from cell membrane to lysosome for destruction or recycling through a series of endosome trafficking Palmitoylation by and this modification, mediated by STT3A, requires JAK1-mediated PD-L1 phosphorylation. CMTM6/CMTM4 binds PD-L1 and maintains its cell surface expression through recycling endosomes but not lysosomal degradation. This process may stabilize PD-L1 by suppressing its ubiquitination. Unacetylated PD-L1 interacts with HIP1R and cargo proteins leading to nuclear translocation through the cytoskeleton and transactivates immune responsive genes to impact the PD-1/PD-L1 blockage treatment response
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