Analysis of CD4+ T-Cell responses to a novel alpha-fetoprotein-derived epitope in hepatocellular carcinoma patients.
OBJECTIVE
Alpha-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.


METHODS
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-gamma.


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.


CONCLUSIONS
Our data will be instrumental in the development of cancer vaccine using AFP-derived immunogens.
Alisa
Akeel
A
Institute of Hepatology, University College London, UK.
Ives
Annette
A
Pathan
Ansar A
AA
Navarrete
Cristina V
CV
Williams
Roger
R
Bertoletti
Antonio
A
Behboudi
Shahriar
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000097:blood* / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D000939:Epitopes / Q000235:genetics / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D008113:Liver Neoplasms / Q000097:blood* / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D000509:alpha-Fetoproteins / Q000235:genetics / Q000276:immunology*
D000939:Epitopes; D006684:HLA-DR Antigens; D000509:alpha-Fetoproteins; D007371:Interferon-gamma