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Li, Chia-Wei; Lim, Seung-Oe; Chung, Ezra M.; Kim, Yong-Soo; Park, Andrew H.; Yao, Jun; Cha, Jong-Ho; Xia, Weiya; Chan, Li-Chuan; Kim, Taewan; Chang, Shih-Shin; Lee, Heng-Huan; Chou, Chao-Kai; Liu, Yen-Liang; Yeh, Hsin-Chih; Perillo, Evan P.; Dunn, Andrew K.; Kuo, Chu-Wei; Khoo, Kay-Hooi; Hsu, Jennifer L.; Wu, Yun; Hsu, Jung-Mao; Yamaguchi, Hirohito; Huang, Tzu-Hsuan; Sahin, Aysegul A.; Hortobagyi, Gabriel N.; Yoo, Stephen S.; Hung, Mien-Chie
Cancer cell, 02/2018, Letnik: 33, Številka: 2Journal Article
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. •N-linked glycosylation is required for physical contact between PD-L1 and PD-1•EGF/EGFR stimulates PD-L1 glycosylation via B3GNT3 glycosyltransferase•Glycosylated-PD-L1 antibody induces PD-L1 internalization•Glycosylated-PD-L1-ADC possesses potent toxicity as well as bystander effects Li et al. show that glycosylation of PD-L1 is essential for PD-L1/PD-1 interaction and immunosuppression in triple-negative breast cancer (TNBC). They generate a glycosylation-specific antibody that induces PD-L1 internalization and an antibody-drug conjugate with potent anti-tumor activities in TNBC models.
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in: SICRIS
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