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Repurposing screen identifies Amlodipine as an inducer of PD-L1 degradation and antitumor immunity

Oncogene volume 40, pages 1128–1146 (2021)Cite this article

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Abstract

Cancer cell expression of PD-L1 leads to T cells exhaustion by transducing co-inhibitory signal, and further understanding the regulation of PD-L1 in cancer cells may provide additional therapeutic strategies. Here by drug repurposing screen, we identified amlodipine as a potent inhibitor of PD-L1 expression in cancer cells. Further survey of calcium-associated pathways revealed calpain-dependent stabilization of the PD-L1 protein. Intracellular calcium delivered an operational signal to calpain-dependent Beclin-1 cleavage, blocking autophagic degradation of PD-L1 accumulated on recycling endosome (RE). Blocking calcium flux by amlodipine depleted PD-L1 expression and increased CD8+ T-cell infiltration in tumor tissues but not in myocardium, causing dose-dependent tumor suppression in vivo. Rescuing PD-L1 expression eliminated the effects of amlodipine, suggesting the PD-L1-dependent effect of amlodipine. These results reveal a calcium-dependent mechanism controlling PD-L1 degradation, and highlight calcium flux blockade as a potential strategy for combinatorial immunotherapy.

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Fig. 1: Amlodipine decreased PD-L1 expression post-translationally by blocking intracellular calcium flux.
Fig. 2: Amlodipine facilitated the autophagic degradation of PD-L1.
Fig. 3: Calpain modulated Beclin-1-dependent stabilization of PD-L1.
Fig. 4: Inactivated calpain facilitated the autophagic degradation of PD-L1 from recycling endosomes.
Fig. 5: Amlodipine suppressed PD-1 binding and growth of tumor cells.
Fig. 6: Amlodipine promoted antitumor immunity by decreasing PD-L1 expression in vivo.
Fig. 7: The calcium flux inhibitor Amlodipine induces PD-L1 degradation by promoting selective autophagy of recycling endosome.

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Data availability

The authors declare that all data supporting the findings of this study are available within the paper and its Supplementary information files.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (No: 82030104, 81874050, 81572326), Basic Research Projects of Shanghai Science and Technology Innovation Action Plan (20JC1410700); National Key R & D Program of China (2016YFC0906002, 2016YFC0906002), Tang Scholar (JX), and Startup Research Funding of Fudan University.

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Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, 200001, Shanghai, China

    Chushu Li, Han Yao, Huanbin Wang & Jing-Yuan Fang

  2. Institutes of Biomedical Sciences, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, China

    Jie Xu

  3. Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, 200001, Shanghai, China

    Jie Xu

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CL, HY, and HW performed experiments and analyzed data. JYF provided supports on study resources. CL and JX wrote the paper. JX conceived the study.

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Li, C., Yao, H., Wang, H. et al. Repurposing screen identifies Amlodipine as an inducer of PD-L1 degradation and antitumor immunity. Oncogene 40, 1128–1146 (2021). https://doi.org/10.1038/s41388-020-01592-6

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