The NKG2D pathway in hepatitis B associated hepatocellular carcinoma in a highly endemic setting (360G-Wellcome-102772_Z_13_Z)

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide; there is an urgent need to better understand mechanisms underlying its immune surveillance to allow their therapeutic manipulation. Animportant pathway implicated in tumour surveillance is the expression of the activatory receptor NKG2D on NK cells, interacting with NKG2D ligands (NKG2DL)induced on cancer cells. I hypothesise that a major factor influencing HCC development and prognosis in the context of chronic hepatitis B virus infection (CHB) is a deficit in NKG2D-mediated NK cell cytotoxicity. This could result from loss of NKG2DL expression by HCC and/or secretion of solubleNKG2D ligands, leading to NKG2D downregulation on NK cells and reduced cytotoxicity. I propose to investigate these mechanisms using direct ex vivo analysis of NKG2D/NKG2DL expression in peripheral blood and liver biopsy samples from a cohort of patients with CHB +/- HCC collected in a high prevalence setting (PROLIFICA study, The Gambia). Functional experiments probing and artificially enhancing NKG2D interactions will be carried out