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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.

Author information

1
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, TX, USA.
2
Key Laboratory of Carcinogenesis and Transformation Research (Ministry of Education), Department of Breast Oncology, Peking University Cancer Hospital & Institute Beijing 100142, P. R. China.
3
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University West Lafayette, IN 47907, USA.
4
Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital Tianjin, P. R. China.
5
Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston Houston, TX, USA.
6
Graduate School of Biomedical Sciences, University of Texas Health Science Center Houston, TX 77030, USA.
7
Center for Molecular Medicine and Graduate Institute of Biomedical Sciences, China Medical University Taichung, Taiwan.

Abstract

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.

KEYWORDS:

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

PMID:
30323975
PMCID:
PMC6176188

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