title: AFP-specific CD4+ helper T-cell responses in healthy donors and HCC patients.
abstract: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and is often diagnosed at an advanced stage. We have investigated alpha-fetoprotein (AFP) as a tumor-associated antigen for HCC. We identified major histocompatibility complex class I-restricted peptide epitopes derived from AFP and studied CD8 T-cell responses in vivo and in vitro in ongoing immunotherapy studies. Helper T cells are of critical importance in shaping the immune response; therefore, we investigated the frequency and function of AFP-specific CD4 T cells in the general population and among HCC patients. CD4 T-cell responses were assessed by direct ex vivo multicytokine enzyme-linked immunospot assay and by measurement of cytokine levels using a multicytokine assay. Our analysis indicates that healthy donors have very low frequencies of AFP-specific CD4 T-cell responses, which are of TH1 type, detectable ex vivo. In contrast, these T cells were either reduced or eliminated in HCC patients at advanced stages of disease. To better activate these cells, we compared the stimulatory capacity of both AFP protein-fed and AdVhAFP-engineered dendritic cells (DC). Healthy donors have CD4 T-cell responses, which were activated in response to AFP protein-fed DC whereas HCC patients do not demonstrate significant responses to AFP protein. AdVhAFP-transduced DC were capable of activating higher frequency TH1 CD4 responses to AFP in both healthy donors and AFP-positive HCC patients. Importantly, CD4 T-cell cytokine expression profiles were skewed towards interleukin-2 and interferon-gamma production when activated by adenovirally engineered DC, which has therapeutic implications for vaccination efforts.
authors: Department of Medicine, Division of Hematology/Oncology , University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
authors: Viktoria N
authors: VN
authors: Evdokimova
authors: Yang
authors: Y
authors: Liu
authors: Douglas M
authors: DM
authors: Potter
authors: Lisa H
authors: LH
authors: Butterfield
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008113:Liver Neoplasms / Q000097:blood / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D010455:Peptides / Q000737:chemistry; D006377:T-Lymphocytes, Helper-Inducer; D000509:alpha-Fetoproteins / Q000096:biosynthesis*
chemical_list: D016207:Cytokines; D010455:Peptides; D000509:alpha-Fetoproteins