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

American Journal of Cancer Research

Chunxiao Liu¹  Seung-Oe Lim²  Bin Shao³  Yun-Ju Lai⁴  Junwei Hou⁵  Chia-Wei Li⁶  Linlin Sun⁷ 

[1]Center for Molecular Medicine and Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan

[2]Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA

[3]Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

[4]Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA

[5]Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston, TX 77030, USA

[6]Key Laboratory of Carcinogenesis and Transformation Research (Ministry of Education), Department of Breast Oncology, Peking University Cancer Hospital Institute, Beijing 100142, P. R. China

[7]Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, P. R. China

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

DOI  :  

学科分类：肿瘤学

来源: e-Century Publishing Corporation

【 摘 要 】

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.

【 授权许可】

CC BY-NC