Comprehensive analysis of the alpha-fetoprotein-specific CD8+ T cell responses in patients with hepatocellular carcinoma.
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. alpha-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.


CONCLUSIONS
In patients with HCC, a high frequency of AFP-specific CD8(+) T cells directed against different epitopes suggest 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.
Thimme
Robert
R
Department of Medicine II, University Hospital Freiburg, Freiburg, Germany. robert.thimme@uniklinik-freiburg.de
Neagu
Michaela
M
Boettler
Tobias
T
Neumann-Haefelin
Christoph
C
Kersting
Nadine
N
Geissler
Michael
M
Makowiec
Frank
F
Obermaier
Robert
R
Hopt
Ulrich T
UT
Blum
Hubert E
HE
Spangenberg
Hans Christian
HC
D000328:Adult; D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000509:alpha-Fetoproteins / Q000378:metabolism*
D018984:Epitopes, T-Lymphocyte; D000509:alpha-Fetoproteins