title: Human dendritic cell maturation by adenovirus transduction enhances tumor antigen-specific T-cell responses.
abstract: Dendritic cells (DCs) have been shown to require a degree of maturation to stimulate antigen-specific, type 1 cytotoxic T lymphocytes in numerous murine models. Limited data in humans suggest that immature DCs (DC) can induce tolerance, yet a variety of nonmatured DC used clinically have induced antigen-specific type 1 T cells in vivo to various tumor-associated antigens. Use of adenovirus to engineer DCs is an efficient method for delivery of entire genes to DC, but the data on the biologic effects of viral transduction are contradictory. The authors demonstrate that DCs transduced with adenovirus (AdV) clearly become more mature by the phenotypic criterion of upregulation of CD83 and downregulation of CD14. Transduced DCs also decrease production of IL-10, and a subset of transduced DCs produce increased levels of IL-12 p70. This level of maturation is superior to that achieved by treatment of these cells with tumor necrosis factor-alpha or interferon-alpha but less pronounced than with CD40L trimer or CD40L + interferon-gamma. Maturation by AdV transduction alone leads to efficient stimulation of antigen-specific T cells from both healthy donors and patients with advanced cancer using two defined human tumor-associated antigens, MART-1 and AFP. Given the pivotal role of DCs in immune activation, it is important to understand the direct biologic effects of AdV on DCs, as well as the impact these biologic changes have on the stimulation of antigen-specific T cells. This study has important implications for the design of DC-based clinical trials.
authors.affiliation: Division of Surgical Oncology, UCLA Medical Center, University of California Los Angeles, USA.
authors.forename: Lana
authors.initials: L
authors.lastname: Schumacher
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.forename: Vivian B
authors.initials: VB
authors.lastname: Dissette
authors.forename: William H
authors.initials: WH
authors.lastname: McBride
authors.forename: Bijay
authors.initials: B
authors.lastname: Mukherji
authors.forename: James S
authors.initials: JS
authors.lastname: Economou
authors.forename: Lisa H
authors.initials: LH
authors.lastname: Butterfield
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D015703:Antigens, CD; D000951:Antigens, Neoplasm / Q000737:chemistry; D023201:CD40 Ligand / Q000737:chemistry; D002986:Clinical Trials as Topic; D003713:Dendritic Cells / Q000166:cytology*; D004797:Enzyme-Linked Immunosorbent Assay; D018014:Gene Transfer Techniques; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry; D016753:Interleukin-10 / Q000737:chemistry; D018664:Interleukin-12 / Q000737:chemistry; D008562:Membrane Glycoproteins / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D010641:Phenotype; D021122:Protein Subunits / Q000737:chemistry; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D000097802:CD83 Antigen
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; D023201:CD40 Ligand; D007136:Immunoglobulins; D016753:Interleukin-10; D018664:Interleukin-12; D008562:Membrane Glycoproteins; D010455:Peptides; D021122:Protein Subunits; D000097802:CD83 Antigen