Comprehensive analysis of the α-Fetoprotein specific CD8+ T cell responses in patients with hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. It has a poor prognosis and only limited therapeutic options are currently available. Thus, the development of new immunotherapeutic strategies is of high clinical priority. α-Fetoprotein (AFP) may be a feasible target antigen since it is highly expressed in the majority of HCCs and since priming of immune responses against AFP results in significant protective antitumoral T-cell responses in the mouse model. However, very 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 in peripheral blood, tumor tissue and non-tumor liver tissue in patients with HCC by using overlapping AFP peptides spanning the entire protein. The AFP specific CD8+ T cell response was also tested in peripheral blood and liver of chronically HCV infected patients and compared to the HCV specific CD8+ T cell response in the same patients. Importantly, the majority of patients with HCC showed AFP-specific CD8+ T cell responses with many responses directed against previously unreported epitope regions. These responses were primarily detectable in the tumor lesions and targeted primarily the c-terminus of the protein. Of note, AFP-specific CD8+ T cells were not limited to patients with HCC since they were also detectable in the peripheral blood and liver of chronically HCV infected patients and to a lesser extent in the peripheral blood of healthy subjects.

Conclusion: Our results show a high frequency of AFP-specific CD8+ T cells directed against several different epitopes in patients with HCC suggesting that AFP has a strong and broad immunogenicity and 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 but also highlight the diversity of responses that may be needed to elicit protective immune responses.