Li et al. showed that glycosylation of PD-L1 (enhanced by epidermal growth factor regulation of B3GNT3 glycotransferase) is required for ligation with the PD-1 receptor and identified monoclonal antibodies that specifically recognize N-linked glycosylated PD-L1. One such antibody caused caveolae-dependent endocytosis and subsequent lysosome degradation of PD-L1, enhancing antitumor immunity in a TNBC mouse model. Conjugating the antibody with a cytotoxic drug further improved antitumor efficacy.
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 beta-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.
Author Info: (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 M
Author Info: (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 Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA. (3) STCube Pharmaceuticals, Inc., 401 Professional Drive, Suite 250, Gaithersburg, MD 20879, USA. (4) STCube Pharmaceuticals, Inc., 401 Professional Drive, Suite 250, Gaithersburg, MD 20879, USA. (5) STCube Pharmaceuticals, Inc., 401 Professional Drive, Suite 250, Gaithersburg, MD 20879, USA. (6) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030, USA. (7) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Korea. (8) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030, USA. (9) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA. (10) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030, USA. (11) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030, USA. (12) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030, USA. (13) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030, USA. (14) Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA. (15) Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA. (16) Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA. (17) Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA. (18) Core Facilities for Protein Structural Analysis, Academia Sinica, Taipei 115, Taiwan; Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan. (19) Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan. (20) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan. (21) Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (22) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030, USA. (23) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030, USA. (24) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030, USA. (25) Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (26) Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (27) STCube Pharmaceuticals, Inc., 401 Professional Drive, Suite 250, Gaithersburg, MD 20879, USA. (28) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 413, Taiwan. Electronic address: mhung@mdanderson.org.
