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Am J Cancer Res. 2018 Sep 1;8(9):1837-1846. eCollection 2018.

Deglycosylation of PD-L1 by 2-deoxyglucose reverses PARP inhibitor-induced immunosuppression in triple-negative breast cancer.

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Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, TX, USA.
Key Laboratory of Carcinogenesis and Transformation Research (Ministry of Education), Department of Breast Oncology, Peking University Cancer Hospital & Institute Beijing 100142, P. R. China.
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University West Lafayette, IN 47907, USA.
Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital Tianjin, P. R. China.
Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston Houston, TX, USA.
Graduate School of Biomedical Sciences, University of Texas Health Science Center Houston, TX 77030, USA.
Center for Molecular Medicine and Graduate Institute of Biomedical Sciences, China Medical University Taichung, Taiwan.


Triple-negative breast cancer (TNBC), the most difficult-to-treat breast cancer subtype, lacks well-defined molecular targets. TNBC has increased programmed death-ligand 1 (PD-L1) expression, and its immunosuppressive nature makes it suitable for immune checkpoint blockade therapy. However, the response rate of TNBC to anti-PD-L1 or anti-programmed cell death protein 1 (PD-1) therapy remains unsatisfactory, as only 10-20% of TNBC patients have a partial response. Glycosylated PD-L1, the functional form of PD-L1, is required for PD-L1-PD-1 interaction. TNBC cells have significantly higher levels of glycosylated PD-L1 than non-TNBC cells do. In a screening of glucose analogs to block PD-L1 glycosylation, we found that 2-deoxyglucose (2-DG) can act as a glucose analog to decrease PD-L1 glycosylation. Because PARP inhibition upregulates PD-L1, 2-DG reduced PARP inhibition-mediated expression of glycosylated PD-L1. The combination of PARP inhibition and 2-DG had potent anti-tumor activity. Together, our results provide a strong rationale for investigating the targeting of PD-L1 glycosylation in TNBC further.


2-DG; 2-deoxyglucose; PARP inhibitor; PD-1; PD-L1; glycosylation; immunosuppression; triple-negative breast cancer


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