Eradication of Triple-Negative Breast Cancer Cells by Targeting Glycosylated PD-L1

Abstract

Protein glycosylation provides proteomic diversity in regulating protein localization, stability, and activity; it remains largely unknown whether the sugar moiety contributes to immunosuppression. In the study of immune receptor glycosylation, we showed that EGF induces programmed death ligand 1 (PD-L1) and receptor programmed cell death protein 1 (PD-1) interaction, requiring β-1,3-N-acetylglucosaminyl transferase (B3GNT3) expression in triple-negative breast cancer. Downregulation of B3GNT3 enhances cytotoxic T cell-mediated anti-tumor immunity. A monoclonal antibody targeting glycosylated PD-L1 (gPD-L1) blocks PD-L1/PD-1 interaction and promotes PD-L1 internalization and degradation. In addition to immune reactivation, drug-conjugated gPD-L1 antibody induces a potent cell-killing effect as well as a bystander-killing effect on adjacent cancer cells lacking PD-L1 expression without any detectable toxicity. Our work suggests targeting protein glycosylation as a potential strategy to enhance immune checkpoint therapy.

EGFR‐ERK pathway regulates CSN6 to contribute to PD‐L1 expression in glioblastoma

“…EGFR‐ERK‐related pathways have been shown to regulate CSN6 expression to stabilize β‐catenin 25 . In addition, EGF could upregulate the expression of B3GNT3 to enhance the stability of PD‐L1 protein in triple‐negative breast cancer 26 . These results demonstrate that the CSN6 regulation through the EGFR‐ERK pathway is crucial for maintaining the protein stabilization in cancer progression.…”

Therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor and anti‐PD‐L1 antibody for treatment of triple‐negative breast cancer

“…Thus, our study provided a novel therapeutic strategy to enhance the efficacy of PD‐L1 targeting therapy in TNBC patients and this combination warrants further clinical investigation. A recent study reported that PD‐L1 undergoes glycosylation in TNBC cells, which leads to immuno‐suppression . Targeting glycosylated‐PD‐L1 using glycosylation‐specific antibody has been proposed as a therapeutic strategy in TNBCs .…”

Homogeneous, Low‐volume, Efficient, and Sensitive Quantitation of Circulating Exosomal PD‐L1 for Cancer Diagnosis and Immunotherapy Response Prediction

“…[6a] However,like most functional proteins,n ative PD-L1 undergoes heavy post-translational modifications,w ith N-linked glycosylation accounting for about 50 %ofthe observed molecular weight. [10] Heavy posttranslational modification makes its polypeptide antigens inaccessible to PD-L1 antibody,a nd ultimately reduces the sensitivity of ELISA-based PD-L1 quantification. [11] Moreover, ELISA is ah eterogeneous reaction taking place on solid-liquid interface,w hich slows binding kinetics and thus requires overnight incubation that further compromises detection sensitivity.F urthermore,E LISA is labor intensive and requires as eries of incubation and washing steps.…”