NKG2D and its ligands: key to immunotherapy of liver cancer?

Hepatocellular carcinoma (HCC) is a common cancer accounting for a significant proportion of all cancers worldwide. Although most cases of HCC occur in countries where hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are endemic, the tumour is ubiquitous and one of the most challenging complications of advanced liver disease. HCC develops deviously and there are currently no reliable biomarkers for early diagnosis. Indeed, because alpha-foetoprotein (AFP) has poor sensitivity and specificity, and other serological markers such as des-gamma-carboxyprothrombin (DCP), and Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) perform only slightly better [1], abdominal ultrasound is presently considered the tool of choice for surveillance of patients at risk. Treatment of HCC has considerably improved over the last few decades from mere surgical resection in a minority of patients with good hepatic function and small tumours to orthotopic liver transplantation in selected patients satisfying the stringent Milan criteria [2], to locoregional ablation procedures, transarterial chemoembolization, and more recently antiangiogenetic drugs that increase survival in patients with advanced HCC for whom no therapy was hitherto available. Targeted treatment options are expected to expand exponentially as specific molecular signatures are being identified for HCC subgroups defined by microarray analysis [3]. Despite the wealth of information on molecular biology, tumour growth rate, surveillance, diagnosis and management, there is currently only a scarcity of seminal studies addressing the immunopathogenesis of HCC, which may have important implications in the design of immunotherapeutic strategies. With respect to adaptive immunity it has been suggested that antigens such as AFP, the melanoma-associated antigen (MAGE), glypican 3 and NY-ESO, which are highly expressed in HCC (reviewed in [4]), are potential targets for T-cell responses. Moreover, several studies suggested that the presence of tumour-infiltrating cytotoxic T-cells is indicative of better survival. Interestingly, treatment of neoplastic nodules with radiofrequency thermal ablation (RFTA) can enhance the release and exposure of tumour antigens, which might help to overcome immune tolerance towards cancer cells [5]. Innate immune responses have only been marginall