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

• Published in: Cancer cell Vol. 33; no. 2; pp. 187 - 201.e10
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.02.2018
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; antibody-drug conjugate; B3GNT3; Cell Line, Tumor; Female; glycosylation; Humans; immune checkpoint blockade; immunosuppression; immunotherapy; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Mice, Inbred BALB C; N-Acetylglucosaminyltransferases - drug effects; N-Acetylglucosaminyltransferases - metabolism; PD-1; PD-L1; Programmed Cell Death 1 Receptor - immunology; receptor internalization; TNBC; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - immunology; Triple Negative Breast Neoplasms - metabolism; antibody-drug conjugate; receptor internalization; immunotherapy; PD-L1; B3GNT3; glycosylation; immunosuppression; TNBC; PD-1; immune checkpoint blockade
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccell.2018.01.009

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.