Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide with a poor prognosis and limited therapeutic options. To aid the development of novel immunological interventions, we studied the breadth, frequency, and tumor‐infiltration of naturally occurring CD8+ T‐cell responses targeting several tumor‐associated antigens (TAA). We used overlapping peptides spanning the entire alpha‐fetoprotein (AFP), glypican‐3 (GPC‐3), melanoma‐associated gene‐A1 (MAGE‐A1) and New York‐esophageal squamous cell carcinoma‐1 (NY‐ESO‐1) proteins and major‐histocompatibility‐complex‐class‐I‐tetramers specific for epitopes of MAGE‐A1 and NY‐ESO‐1 to analyze TAA‐specific CD8+ T‐cell responses in a large cohort of HCC patients. After nonspecific expansion in vitro, we detected interferon‐γ (IFN‐γ)‐producing CD8+ T cells specific for all four TAA in the periphery as well as in liver and tumor tissue. These CD8+ T‐cell responses displayed clear immunodominance patterns within each TAA, but no consistent hierarchy was observed between different TAA. Importantly, the response breadth was highest in early‐stage HCC and associated with patient survival. After antigen‐specific expansion, TAA‐specific CD8+ T cells were detectable by tetramer staining but impaired in their ability to produce IFN‐γ. Furthermore, regulatory T cells (Treg) were increased in HCC lesions. Depletion of Treg from cultures improved TAA‐specific CD8+ T‐cell proliferation but did not restore IFN‐γ‐production. Conclusion: Naturally occurring TAA‐specific CD8+ T‐cell responses are present in patients with HCC and therefore constitute part of the normal T‐cell repertoire. Moreover, the presence of these responses correlates with patient survival. However, the observation of impaired IFN‐γ production suggests that the efficacy of such responses is functionally limited. These findings support the development of strategies that aim to enhance the total TAA‐specific CD8+ T‐cell response by therapeutic boosting and/or specificity diversification. However, further research will be required to help unlock the full potential of TAA‐specific CD8+ T‐cell responses. (Hepatology 2014;59:1415‐1426)

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide with an increasing incidence. The clinical outcome is influenced by the underlying liver cirrhosis, the size of the tumour at the time of diagnosis and the few therapeutic options currently available. In recent years there has been a lot of progress in the understanding of HCC immunobiology. This review summarizes our current knowledge of HCC biology, the role of chronic inflammation in carcinogenesis and the role of tumour-specific immune responses. Furthermore, we will present potentially new, immune-based therapies that might open up new avenues for the treatment of HCC.