title: Lack of ex vivo peripheral and intrahepatic α-fetoprotein-specific CD4+ responses in hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) is one of the most common malignancies with a poor prognosis and limited therapeutic options that is often characterized by the expression of the tumor-associated antigen α-fetoprotein (AFP). CD4+ helper T cells are important in generating potent anticancer immunity as they prime and expand CD8+ T-cell memory and may also have direct antitumor activity. However, very little information is currently available about the relative frequency, immunodominance and peripheral versus intratumoral distribution of AFP-specific CD4+ T-cell responses in patients with HCC. We, therefore, analyzed AFP-specific CD4+ responses in blood and tumor tissue of patients with HCC by using overlapping peptides spanning the entire AFP protein and novel sensitive approaches such as antigen-specific upregulation of CD154. We found that AFP-specific CD4+ T-cell responses were not detectable in the peripheral blood ex vivo. However, after in vitro stimulation, AFP-specific CD4+ T-cell responses were detectable in a large fraction of patients targeting different previously unreported epitopes with no clear immunodominance. These results indicate that AFP-specific CD4+ T-cell responses are not completely deleted but only present at very low frequencies. Importantly, AFP-specific CD4+ T-cell responses were also rarely detectable in tumor tissue, suggesting that the relative absence of these cells in the circulation ex vivo is not due to a rapid accumulation to the tumor side. Taken together, these results suggest that the lack of sufficient CD4+ T-cell help, especially within the tumor tissue, may be one central mechanism responsible for the failure of AFP-specific immune responses to control HCC progression.
authors.affiliation: Department of Medicine II, University of Freiburg, Freiburg, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Witkowski
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Spangenberg
authors.forename: Christoph
authors.initials: C
authors.lastname: Neumann-Haefelin
authors.forename: Nico
authors.initials: N
authors.lastname: Büttner
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Breous
authors.forename: Nadine
authors.initials: N
authors.lastname: Kersting
authors.forename: Oliver
authors.initials: O
authors.lastname: Drognitz
authors.forename: Ulrich T
authors.initials: UT
authors.lastname: Hopt
authors.forename: Hubert E
authors.initials: HE
authors.lastname: Blum
authors.forename: Nasser
authors.initials: N
authors.lastname: Semmo
authors.forename: Robert
authors.initials: R
authors.lastname: Thimme
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000276:immunology / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000378:metabolism; D015331:Cohort Studies; D000939:Epitopes / Q000276:immunology; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D008113:Liver Neoplasms / Q000276:immunology* / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000138:chemical synthesis / Q000276:immunology; D000509:alpha-Fetoproteins / Q000737:chemistry / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D000939:Epitopes; D010455:Peptides; D000509:alpha-Fetoproteins; D023201:CD40 Ligand; D007371:Interferon-gamma