Abstract
Activated hepatic stellate cells (aHSCs) are now established as a central driver of fibrosis in human liver injury. In the presence of chronic or repeated injury, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) can occur, so there is interest in down-regulating aHSCs activity in order to treat these diseases. Here, we report that Vγ9Vδ2 T cells are reduced in patients with liver cirrhosis, stimulating us to investigate possible interactions between Vγ9Vδ2 T cells and aHSCs. We find that Vγ9Vδ2 T cells kill aHSCs and killing is enhanced when aHSCs are pretreated with BPH-1236, a lipophilic analog of the bone resorption drug zoledronate. Cytotoxicity is mediated by direct cell-to-cell contact as shown by Transwell experiments and atomic force microscopy, with BPH-1236 increasing the adhesion between aHSCs and Vγ9Vδ2 T cells. Mechanistically, BPH-1236 functions by inhibiting farnesyl diphosphate synthase, leading to accumulation of the phosphoantigen isopentenyl diphosphate and recognition by Vγ9Vδ2 T cells. The cytolytic process is largely dependent on the perforin/granzyme B pathway. In a Rag2−/−γc−/− immune-deficient mouse model, we find that Vγ9Vδ2 T cells home-in to the liver, and when accompanied by BPH-1236, kill not only orthotopic aHSCs but also orthotopic HCC tumors. Collectively, our results provide the first proof-of-concept of a novel immunotherapeutic strategy for the treatment of fibrosis–cirrhosis–HCC diseases using adoptively transferred Vγ9Vδ2 T cells, combined with a lipophilic bisphosphonate.
Highlights
Cirrhosis is an advanced stage of liver fibrosis and remains one of the central challenges in clinical hepatology
We evaluated cytotoxicity by monitoring the release of an lactate dehydrogenase (LDH) marker [20] and found that Activated hepatic stellate cells (aHSCs) were killed by ex vivo-expanded Vγ9Vδ2 T cells from healthy donors
Building from our discovery that zoledronate can enhance the killing of aHSCs by Vγ9Vδ2 T cells, we explored the possibility that the lipophilic bisphosphonates might have translational potential as lead compounds for treating liver disease
Summary
Cirrhosis is an advanced stage of liver fibrosis and remains one of the central challenges in clinical hepatology. Fibrosis results from the excessive accumulation of extracellular matrix (ECM) proteins (e.g., collagen) at sites of tissue repair [1, 2]. ECM proteins are produced by activated hepatic stellate cells (aHSCs), which represent ~10% of all liver cells [3]. HSCs are activated following liver injury, and transdifferentiate from quiescent lipocytes into ECM-producing myofibroblasts [4]. This transdifferentiation process can drive fibrogenesis [4], and sustained fibrogenesis leads to cirrhosis.
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