The role of the TIGIT immune checkpoint axis in susceptibility to infection in decompensated cirrhosis

One in ten people in the UK have liver disease and the progressive development of liver damage can lead ultimately to cirrhosis. Patients with cirrhosis can remain well for many years but a proportion will develop complications such as ascites (fluid in the abdomen), upper gastrointestinal bleeding, encephalopathy (a state of confusion), or jaundice. This is called decompensated cirrhosis and if this causes other organs in the body to fail then it is termed acute-on-chronic liver failure. One of the most profound consequences of decompensated cirrhosis and acute-on-chronic liver failure is that patients are highly susceptible to infections. Infections in these patients have a very poor prognosis with a high mortality, even with antibiotic treatment. Therefore it is important to try to understand why these patients are more susceptible to infections in the first place so we can develop new treatments.

An interesting observation in patients with decompensated cirrhosis is that although their immune system is highly activated, the immune cells do not fight infections well. Our theory is that this, in part, is because the cells have a higher level of a type of molecule called immune checkpoints. Immune checkpoints act as the "brake" on the immune system and while they can be helpful to prevent damage from an over-active immune system, too much can hamper the immune system's ability to fight diseases. Cancer cells have higher levels of immune checkpoints and a new type of cancer treatment ("immunotherapy") works by blocking immune checkpoints.

We are interested in a particular group of immune checkpoints collectively called the "TIGIT axis" on T cells, a key type of immune cell that fights infections and coordinates immune responses. These immune checkpoints have been shown to impair T cell function against cancer and chronic viral infections (like HIV). To investigate our theory that they are also involved in poor T cell functions in decompensated liver disease, we will look at the levels of the TIGIT axis immune checkpoints on T cells that we find in blood, the liver, and in ascites (the fluid that collects in the abdomen). We will then go on to investigate if having more of these immune checkpoints makes the T cells less effective, and if we can improve this by blocking the immune checkpoints.

We will recruit patients from outpatient clinics or who are admitted to hospital. With their consent we will collect samples of blood and ascites, and collect data about their medical history and medication. If they have a liver biopsy to diagnose their condition, then we will ask to use part of the sample. We will follow them up for up to 1 years after they join the study.

Overall, the intended benefit is that if we can identify a particular immune checkpoint then it could be a target for new medication to reset the immune system in patients with decompensated cirrhosis and reduce their susceptibility to infection.

Patients with decompensated cirrhosis and acute-on-chronic liver failure are highly susceptible to infections and the prognosis from these infections is very poor. The widespread use of antibiotics is leading to multi-drug resistant microbes and so new treatment strategies are urgently needed. Patients with decompensated cirrhosis and ACLF are observed to have impaired T cell function but the mechanisms underlying this are not fully understood.

The TIGIT immune checkpoint axis includes inhibitory (TIGIT and CD96) and stimulatory (CD226) immune checkpoints that are key regulators of T cell function. They bind a shared ligand, CD155, which exists in a soluble form as well as membrane-bound on myeloid cells. We have shown that CD4+ and CD8+ T cells from patients with decompensated cirrhosis express more TIGIT and CD96, suggesting the TIGIT axis mediates T cell dysfunction in decompensated cirrhosis.

The proposed experiments will fully assess TIGIT axis expression on immune cells in blood, ascites and liver of patients with decompensated cirrhosis and ACLF using flow cytometry and tissue staining. We will use ELISA assays to measure levels of soluble CD155 in plasma and ascites, and use recombinant soluble CD155 to establish whether it influences T cell function via the TIGIT axis. We will then use in vitro T cells functional assays to establish whether blocking TIGIT and CD96 improves T cell dysfunction.

This project will elucidate the role of the TIGIT axis in T cell dysfunction in patients with decompensated cirrhosis and ACLF, and thus identify therapeutic targets to reconstitute the host immunity and improve clinical outcomes for these patients.