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Repurposing screen identifies Amlodipine as an inducer of PD-L1 degradation and antitumor immunity
Chushu Li1, Han Yao1, Huanbin Wang1
1Division 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.
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.
Insights
Amlodipine inhibits programmed death-ligand 1 (PD-L1) expression in cancer cells by blocking calcium flux, enhancing anti-tumor T-cell responses and suppressing tumor growth. This reveals a novel therapeutic strategy for cancer immunotherapy.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Programmed death-ligand 1 (PD-L1) on cancer cells inhibits T-cell responses, contributing to tumor immune evasion.
- Understanding PD-L1 regulation in cancer is crucial for developing effective immunotherapies.
Purpose of the Study:
- To identify novel inhibitors of PD-L1 expression in cancer cells.
- To elucidate the regulatory mechanisms of PD-L1 expression and its link to calcium signaling.
- To evaluate amlodipine as a potential therapeutic agent for cancer immunotherapy.
Main Methods:
- Drug repurposing screen to identify PD-L1 inhibitors.
- Investigation of calcium-dependent pathways regulating PD-L1 protein stability.
- Assessment of amlodipine's effects on PD-L1 expression, T-cell infiltration, and tumor suppression in vivo.
Main Results:
- Amlodipine was identified as a potent inhibitor of PD-L1 expression in cancer cells.
- Calcium signaling, via calpain and Beclin-1 cleavage, was found to stabilize PD-L1 by inhibiting autophagy.
- Amlodipine treatment reduced PD-L1, increased CD8+ T-cell infiltration in tumors, and suppressed tumor growth without cardiac toxicity.
Conclusions:
- A calcium-dependent mechanism regulates PD-L1 degradation through the autophagy pathway.
- Blocking calcium flux with amlodipine depletes PD-L1, enhancing anti-tumor immunity and tumor suppression.
- Calcium flux blockade represents a promising strategy for combinatorial cancer immunotherapy.
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