title: Maturation pathways of dendritic cells determine TAP1 and TAP2 levels and cross-presenting function.
abstract: Ability to cross-present exogenous antigens in the human leukocyte antigen class I pathway is key to the antigen presenting function of mature tumor cell-loaded dendritic cells (DC). Conditions of DC maturation have been shown to be important for DCs ability to produce proinflammatory cytokines and induce T cell effector functions. However, it remains unknown if the different pathways of maturation are associated with modulation of the ability of mature DCs to cross-present tumor antigens (TA). Here, we compare DC matured with 3 clinically relevant cytokine combinations including interleukin (IL)-1 beta, tumor necrosis factor-alpha, IL-6 (termed DC-0), DC-0 cells incubated with prostaglandin-2 (termed DC-0+prostaglandin-2), or DC treated with interferon-gamma, interferon-alpha, tumor necrosis factor-alpha, Poly I:C, and IL1-beta (termed DC-1). We found that these DC vary in their ability to cross-present TA to cytotoxic T lymphocytes (CTL), with the DC-1 cytokine combination being significantly more effective than the other 2. TA cross presentation and CTL priming were strongly correlated with level of expression of the antigen processing machinery components, TAP1 and TAP2, indicating that these components could be used as biomarkers to standardize DC preparations for optimal function. However, the up-regulation of TAP1/TAP2 was not sufficient to explain the enhanced cross-presentation ability of DC-1 cells, as the use of IFN-gamma alone to up-regulate TAP1/TAP2 did not generate DC as effective at cross-presentation as the full DC-1 maturation cytokine combination. These data indicate for the first time that the pathways of DC maturation modulate antigen processing machinery component expression to different extents and that differently matured DC vary in the ability to cross-present TA to human leukocyte antigen class I-restricted CTL.
authors.affiliation: Department of Otolaryngology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Andrés
authors.initials: A
authors.lastname: López-Albaitero
authors.forename: Robbie
authors.initials: R
authors.lastname: Mailliard
authors.forename: Trevor
authors.initials: T
authors.lastname: Hackman
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Andrade Filho
authors.forename: Xinhui
authors.initials: X
authors.lastname: Wang
authors.forename: William
authors.initials: W
authors.lastname: Gooding
authors.forename: Soldano
authors.initials: S
authors.lastname: Ferrone
authors.forename: Pawel
authors.initials: P
authors.lastname: Kalinski
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ferris
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019496:Cancer Vaccines; D018288:Carcinoma, Small Cell / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D015234:HLA-A Antigens / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D008213:Lymphocyte Activation; D058965:MART-1 Antigen; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D009363:Neoplasm Proteins / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D016207:Cytokines; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; C072013:MAGEA3 protein, human; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D011453:Prostaglandins; C073119:TAP1 protein, human; C071692:TAP2 protein, human