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Targeted attenuation of liver fibrosis using microbubble-enhanced protease-activated receptor 1 chimeric antigen
Hao-Chien Hung1, Ainani Priza Minhalina2, Po-Jung Hsu3
1Department of General Surgery, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan; Chang Gung University College of Medicine, Taoyuan, Taiwan.
Background:
Liver diseases account for a significant global mortality rate, with hepatic fibrosis representing a critical precursor to cirrhosis and liver cancer. Current therapeutic options remain limited, as no antifibrotic drugs have received FDA approval. In this study, we propose a novel CAR-T cell strategy targeting protease-activated receptor 1 (PAR1) on activated hepatic stellate cells (aHSCs) to combat liver fibrosis.
Methods:
By engineering CAR-T cells specifically against PAR1, we aimed to selectively eliminate PAR1-expressing HSCs and thereby inhibit PAR1-dependent fibrogenesis. To enhance CAR-T cell delivery into the fibrotic liver microenvironment, we employed ultrasound-mediated delivery with microbubbles (USMB) in a Carbon tetrachloride (CCl4)-induced liver fibrosis mouse model.
Findings:
Our results demonstrated that PAR1CAR-T cells effectively eliminated PAR1-expressing HSCs in vitro. In animals, USMB significantly enhanced CAR-T cell penetration, migration, and intrahepatic retention within the fibrotic liver microenvironment. Blockade of PAR1 signaling suppressed HSC activation, attenuated fibrogenesis, and reduced fibrosis progression. Mechanistically, activation of the TGF-β/p-SMAD2/3 axis was accompanied by upregulation of PAR1 on activated HSCs, and this fibrogenic axis was attenuated by the targeted elimination of PAR1-expressing HSCs.
Interpretation:
Collectively, USMB-mediated PAR1CAR-T cell therapy demonstrated potent antifibrotic efficacy by enhancing CAR-T cell delivery and intrahepatic retention in the liver, offering a promising antifibrotic immunotherapy approach for patients with liver fibrosis.
Insights
This study introduces a new CAR-T cell therapy targeting PAR1 to treat liver fibrosis. Ultrasound-mediated delivery enhanced CAR-T cell effectiveness, showing promise for a novel antifibrotic immunotherapy.
Area of Science:
- Immunotherapy
- Hepatology
- Cellular Biology
Background:
- Liver diseases and hepatic fibrosis contribute significantly to global mortality.
- Current treatments for liver fibrosis are limited, with no FDA-approved antifibrotic drugs.
- Activated hepatic stellate cells (aHSCs) expressing protease-activated receptor 1 (PAR1) are key drivers of fibrosis.
Purpose of the Study:
- To develop a novel CAR-T cell strategy targeting PAR1 on aHSCs for liver fibrosis treatment.
- To evaluate the efficacy of ultrasound-mediated microbubble delivery (USMB) for enhancing CAR-T cell therapy in a liver fibrosis model.
Main Methods:
- Engineered CAR-T cells to target PAR1 on aHSCs.
- Utilized USMB for enhanced delivery of CAR-T cells into the fibrotic liver microenvironment.
- Employed a Carbon tetrachloride (CCl4)-induced liver fibrosis mouse model.
Main Results:
- PAR1CAR-T cells effectively eliminated PAR1-expressing HSCs in vitro.
- USMB significantly improved CAR-T cell penetration, migration, and retention in fibrotic livers.
- PAR1 blockade and CAR-T cell therapy attenuated fibrogenesis and reduced fibrosis by inhibiting the TGF-β/p-SMAD2/3 axis.
Conclusions:
- USMB-mediated PAR1CAR-T cell therapy shows potent antifibrotic efficacy.
- This approach enhances CAR-T cell delivery and retention in the liver.
- Offers a promising new immunotherapy for liver fibrosis.
