The role of LLT1 in immune evasion and hepatocellular carcinoma
Research type
Research Study
Full title
The role of LLT1 in immune evasion and hepatocellular carcinoma
IRAS ID
169524
Contact name
Ruth Nicholson
Contact email
Sponsor organisation
Imperial College London and Imperial College Healthcare NHS Trust
Clinicaltrials.gov Identifier
15/LO/0363, NRES Committee London - City & Easy
Duration of Study in the UK
3 years, 0 months, 0 days
Research summary
Summary of Research
This is an observational laboratory based study on samples taken from individuals with primary or secondary liver cancer and patients with chronic liver disease, and healthy volunteers.
The study will aim to define the immunology of hepatocellular carcinoma (HCC), the role and significance of lectin-like transcript-1 in hepatocellular carcinoma and the potential significance of circulating free DNA in hepatocellular carcinoma.
Tissue including liver tissue, buccal swabs and blood will be obtained from patients undergoing clinical procedures for primary or secondary liver cancer as part of their routine care. We will also seek to take blood and buccal swabs from patients with other liver diseases and healthy volunteers.
Summary of Results
Natural Killer (NK) cells within the blood stream and in tissues of the body have vital roles in anti-viral responses and cancer surveillance through their cell-killing abilities. Furthermore, they support anti-bacterial immune responses through the production of chemicals required to recruit other white blood cells. However, liver cirrhosis renders patients susceptible to infections and liver cancer. Here, we demonstrate NK cells in liver cirrhosis have functional deficits with an inhibitory immune profile. These findings are further accentuated in liver cancer.
A novel group of NK cells was discovered within the blood stream of patients with liver cirrhosis and liver cancer, with an inhibitory, immature, liver–homing profile. This inhibitory group of NK cells were expanded in patients with liver cirrhosis and liver cancer and demonstrated attenuated cell-killing responses and a reduced ability to produce chemicals to aid a robust immune response to infections, compared to cells from healthy volunteers.
Furthermore, we have demonstrated that a marker, LLT1, is overexpressed in liver tissue in patients with cirrhosis. It interacts with CD161, a receptor upregulated on the surface of NK cells in cirrhosis, and this CD161-LLT1 interaction suppresses the cell-killing ability of NK cells.
This research helps aid understanding NK cell alterations in cirrhosis and underlying mechanisms resulting in failures of NK cell cancer surveillance. NK cells are promising targets to manipulate for immunotherapies, and given that patients with liver cirrhosis are at a higher risk of liver cancer, carefully delineating pre-existing alterations to NK cells in cirrhosis is imperative to understanding how to manipulate NK cells for immunotherapy purposes. Furthermore, having identified the CD161-LLT1 interaction as an important inhibitory pathway in cirrhosis, this research opens up avenues to investigate the CD161-LLT1 interaction as a promising potential target for immunotherapy development. Furthermore, recurrent infections and fatal sepsis is often an outcome that our patients with cirrhosis face. This research identifies another immune cell, NK cells, that are dysfunctional in cirrhosis and identifies a lack of adequate interferon production by NK cells to support robust anti-bacterial immune responses. This research helps broaden our understanding of immune dysfunction in cirrhosis.REC name
London - City & East Research Ethics Committee
REC reference
15/LO/0363
Date of REC Opinion
23 Apr 2015
REC opinion
Further Information Favourable Opinion