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

Authors

Chia-Wei Li1, Seung-Oe Lim1,12, Ezra M. Chung11, Yong-Soo Kim11, Andrew H. Park11, Jun Yao1, Jong-Ho Cha1,4, Weiya Xia1, Li-Chuan Chan1,5, Taewan Kim1, Shih-Shin Chang1, Heng-Huan Lee1, Chao-Kai Chou1, Yen-Liang Liu6, Hsin-Chih Yeh6, Evan P. Perillo6, Andrew K. Dunn6, Chu-Wei Kuo7,8, Kay-Hooi Khoo8, Jennifer L. Hsu1,9, Yun Wu2, Jung-Mao Hsu1, Hirohito Yamaguchi1, Tzu-Hsuan Huang1, Aysegul A. Sahin2, Gabriel N. Hortobagyi3, Stephen S. Yoo11, Mien-Chie Hung1,5,9,10

Organizations

1. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030, USA
2. Department of Pathology
3. Department of Breast Medical Oncology The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
4. Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Korea
5. Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
6. Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA
7. Core Facilities for Protein Structural Analysis
8. Institute of Biological Chemistry Academia Sinica, Taipei 115, Taiwan
9. Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan
10. Department of Biotechnology, Asia University, Taichung 413, Taiwan
11. STCube Pharmaceuticals, Inc., 401 Professional Drive, Suite 250, Gaithersburg, MD 20879, USA
12. Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA

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.

CovalX Technology Used (Click each option to learn more)

Epitope Mapping

HM4

Outcomes

The epitopes of mouse monoclonal gPD-L1 antibodies STM004 and STM108 were both mapped. 5 μl of the antigen sample was combined with 5 μl of the antibody sample, giving a final concentration of 2 μM/1 μM. Cross-linkers and other chemicals were added to the solution before allowing crystallization. The samples were analyzed using the CovalX HM4 detection system.

Source

https://doi.org/10.1016/j.ccell.2018.01.009