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Clofibrate inhibits tumor immune escape by increasing macrophage phagocytosis
Huijie Wang1, Yelei Wang1, Yinghan Li1
1School of Life Science, Jiangsu University, Zhenjiang, Jiangsu Province, 212013, People's Republic of China.
Abstract:
The CD47/SIRPα signaling axis functions as a critical innate immune checkpoint, enabling tumor immune escape. Although the PPARα agonist clofibrate is known to influence cancer cell metabolism, proliferation, and inflammatory responses, its specific effect on macrophage-mediated phagocytosis of cancer cells has not been determined. In this study, we found that clofibrate downregulates CD47 in lung cancer cells through reductions in gene expression, membrane protein levels, and transcriptional activity. This downregulation thereby promoted macrophage phagocytosis. Using in vivo tumor models, we further demonstrated that clofibrate limits immune escape and exhibits significantly enhanced anti-tumor efficacy when combined with an anti-CD47 antibody. Mechanistically, the inhibition of CD47 by clofibrate was dependent on PPARα, as evidenced by its reversal upon PPARα silencing. Together, these results uncover a novel mechanism through which clofibrate restricts tumor immune escape by transcriptional suppression of CD47.
Insights
The PPARα agonist clofibrate reduces CD47 expression in lung cancer cells, promoting macrophage phagocytosis. This finding enhances anti-tumor efficacy, particularly when combined with CD47-blocking antibodies, offering a new strategy against tumor immune escape.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- The CD47/SIRPα axis is a key immune checkpoint allowing tumors to evade detection.
- Clofrarate, a PPARα agonist, affects cancer cell metabolism and inflammation, but its impact on phagocytosis is unknown.
Purpose of the Study:
- To investigate the effect of clofibrate on CD47 expression and macrophage phagocytosis in lung cancer.
- To elucidate the mechanism underlying clofibrate's action on CD47.
Main Methods:
- Downregulation of CD47 in lung cancer cells by clofibrate.
- Assessment of macrophage phagocytosis of cancer cells.
- In vivo tumor models to evaluate anti-tumor efficacy.
- PPARα silencing to determine mechanism.
Main Results:
- Clofrarate significantly reduced CD47 gene expression, protein levels, and transcriptional activity in lung cancer cells.
- This CD47 downregulation enhanced macrophage-mediated phagocytosis.
- In vivo, clofibrate combined with anti-CD47 antibodies showed superior anti-tumor effects.
- Clofrarate's inhibition of CD47 was dependent on PPARα activity.
Conclusions:
- Clofrarate suppresses CD47 expression transcriptionally, thereby reducing tumor immune escape.
- This mechanism highlights a novel therapeutic strategy involving PPARα agonists and CD47 blockade for cancer treatment.
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