Journal
CANCER CELL
Volume 33, Issue 2, Pages 187-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2018.01.009
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Funding
- NIH [CCSG CA016672, R21 CA193038]
- Cancer Prevention Research Institute of Texas [RP160710]
- National Breast Cancer Foundation
- Breast Cancer Research Foundation [BRCF-17-069]
- Patel Memorial Breast Cancer Endowment Fund
- University of Texas MD Anderson-China Medical University and Hospital Sister Institution Fund
- Ministry of Health and Welfare, China Medical University Hospital Cancer Research Center of Excellence [MOHW106-TDU-B-212-144003]
- Center for Biological Pathways
- Susan G. Komen for the Cure Postdoctoral Fellowship [PDF12231298]
- Basic Science Research Program through the National Research Foundation of Korea - Korean government (MSIP) [NRF-2011-357-C00140]
- National Research Foundation of Korea grant for the Global Core Research Center - Korean government (MSIP) [2011-0030001]
- NATIONAL CANCER INSTITUTE [R21CA193038, P30CA016672] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING [T32EB007507] Funding Source: NIH RePORTER
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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.
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