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The role of LLT1 in the liver and in hepatocellular carcinoma.

Naveenta Kumar

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Wellcome Trust (WT)
Understanding the mechanisms underlying immune evasion by tumours is a focus of intense research and critical to the development of novel anti-cancer therapies. Our preliminary data show that lectin-like transcript 1 (LLT1) is upregulated in hepatocellular carcinoma (HCC), and that the LLT1-CD161 interaction inhibits NK cell cytotoxicity. CD16 is expressed on the majority of NK cells and a subset of CD8+ T cells enriched in the liver. We propose that upregulation of LLT1 represents a novel mecha nism by which HCC evades immune recognition by NK cells. Here we propose to investigate: 1. LLT1 expression in the liver during disease with specific emphasis on HCC. This will be achieved by immunohistochemistry of liver resections/biopsies and in vitro stimulation of primary hepatocytes. 2. The molecular mechanisms by which CD161 engagement affects NK and T cell responses, specifically the structure of the immune synapse and cytoskeleton, as well as the effects on signalling pathways and l ymphocyte effector functions. 3. If LLT1 expression promotes survival of HCC cells by reducing the efficacy of anti-tumour NK functions, using PBMCs and liver resident NK cells derived from both healthy individuals and HCC patients.

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