Analysis of CD4+ T-Cell Responses to a Novel α-Fetoprotein-Derived Epitope in Hepatocellular Carcinoma Patients

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Abstract
Purpose: α-Fetoprotein (AFP) is a tumor-associated antigen in hepatocellular carcinoma and is a target for the development of cancer vaccine. Four immunodominant AFP-derived HLA-A*0201-restricted peptides have been identified and the administration of these peptides with an adjuvant has stimulated AFP-specific CTL responses in hepatocellular carcinoma patients. However, no AFP-derived CD4 T-cell epitope has yet been reported and the status of AFP-specific CD4+ T-cell responses in hepatocellular carcinoma patients is not fully understood. The aim of this study was to analyze naturally occurring CD4+ T-cell responses to AFP. Experimental Design: We analyzed the ability of CD4+ T cells to recognize an HLA-DR-restricted AFP-derived epitope in 41 hepatocellular carcinoma patients and 24 non-hepatocellular carcinoma control patients using intracellular cytokine assays for IFN-γ. Results: Here, for the first time, we report the identification of an AFP-derived CD4+ T-cell epitope that is recognized by circulating lymphocytes from hepatocellular carcinoma patients in association with HLA-DR. The absence of detectable responses in healthy donors and patients with chronic liver disease suggests that AFP-specific CD4+ T cells in the responder patients had been previously expanded in vivo in response to the tumor. The anti-AFP CD4+ T-cell response was only detected in hepatocellular carcinoma patients with normal or mildly elevated serum AFP levels who were in the early stage of disease. Conclusion: Our data will be instrumental in the development of cancer vaccine using AFP-derived immunogens.
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