Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide, with a poor prognosis and limited therapeutic options. Therefore, the development of novel therapeutic strategies is of high priority. ␣-Fetoprotein (AFP) is overexpressed in the majority of HCCs. Priming of immune responses against AFP results in significant protective antitumoral T cell responses in the mouse model. Little information is available about the hierarchy, breadth, frequency, and peripheral versus intrahepatic distribution of AFP-specific CD8 ؉ T cell responses in patients with HCC. To address these important issues we comprehensively analyzed CD8 ؉ T cell responses against full-length AFP in peripheral blood, tumor liver tissue, and nontumor liver tissue from patients with HCC using overlapping AFP peptides. The AFP-specific CD8 ؉ T cell response was also tested in peripheral blood and liver from patients chronically infected with hepatitis C virus (HCV) and compared to the HCV-specific CD8 ؉ T cell response. The majority of patients with HCC showed AFP-specific responses, with many responses directed against previously unreported epitopes. These responses were primarily detectable in the HCC tissue and mainly targeted the C-terminus of AFP. Interestingly, AFP-specific T cells were not only found in patients with HCC but also in patients with chronic HCV infection, other liver diseases, and less frequently in healthy subjects. Conclusion: In patients with HCC, a high frequency of AFPspecific CD8 ؉ T cells directed against different epitopes suggests that AFP has a strong and broad immunogenicity. Further, CD8 ؉ T cells specific for the self-antigen AFP are present in the normal T cell repertoire and are not centrally or peripherally deleted. Our results provide support for strategies to boost AFP-specific CD8 ؉ T cell responses in patients with HCC but also demonstrate a diversity of immune responses that may be needed for protection. (HEPATOLOGY 2008; 48:1821-1833.)
H epatocellular carcinoma (HCC) is one of the most common tumors in the world, with a global incidence of 500,000 new cases per year. 1 HCC is up to four times more common in men than in women and 60%-90% of these tumors develop in a cirrhotic liver. If untreated, most patients die within 3-6 months after diagnosis and, even if treated, the 5-year survival rate is low. [1][2][3] Therefore, new strategies to treat patients with HCC have a high clinical priority. Immunotherapy aimed at inducing or activating HCC-specific immune responses is one such concept; its rationale is based on the presence of high numbers of tumor-infiltrating T cells in HCC tissue, 4 the correlation between the density of lymphocytic infiltrates in HCC lesions and prognosis, 5,6 and most importantly, the finding that adoptive immunotherapy with anti-CD3 and interleukin-2 (IL-2) stimulated autologous lymphocytes lowers postsurgical HCC recurrence rates in humans. 7