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

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

Oncogene (2020-12-17)
Chushu Li, Han Yao, Huanbin Wang, Jing-Yuan Fang, Jie Xu
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Cycloheximide, Biotechnology Performance Certified
Sigma-Aldrich
3-Methyladenine, autophagy inhibitor
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Chloroquine diphosphate salt, powder or crystals, 98.5-101.0% (EP)
Nunc® Lab-Tek® Chamber Slide system, 8 wells, Permanox® slide, 0.8 cm2/well, sterile, 96/cs
Sigma-Aldrich
Thapsigargin, ≥98% (HPLC), solid film
Sigma-Aldrich
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Sigma-Aldrich
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