title: Processing and cross-presentation of individual HLA-A, -B, or -C epitopes from NY-ESO-1 or an HLA-A epitope for Melan-A differ according to the mode of antigen delivery.
abstract: The ability of dendritic cells (DCs) to cross-present protein tumor antigens to cytotoxic T lymphocytes (CTLs) underpins the success of therapeutic cancer vaccines. We studied cross-presentation of the cancer/testis antigen, NY-ESO-1, and the melanoma differentiation antigen, Melan-A by human DC subsets. Monocyte-derived DCs (MoDCs) efficiently cross-presented human leukocyte associated (HLA)-A2-restricted epitopes from either a formulated NY-ESO-1/ISCOMATRIX vaccine or when either antigen was mixed with ISCOMATRIX adjuvant. HLA-A2 epitope generation required endosomal acidification and was proteasome-independent for NY-ESO-1 and proteasome-dependent for Melan-A. Both MoDCs and CD1c(+) blood DCs cross-presented NY-ESO-1-specific HLA-A2(157-165)-, HLA-B7(60-72)-, and HLA-Cw3(92-100)-restricted epitopes when formulated as an NY-ESO-1/ISCOMATRIX vaccine, but this was limited when NY-ESO-1 and ISCOMATRIX adjuvant were added separately to the DC cultures. Finally, cross-presentation of NY-ESO-1(157-165)/HLA-A2, NY-ESO-1(60-72)/HLA-B7, and NY-ESO-1(92-100)/HLA-Cw3 epitopes was proteasome-dependent when formulated as immune complexes (ICs) but only proteasome-dependent for NY-ESO-1(60-72)/HLA-B7-restricted cross-presentation facilitated by ISCOMATRIX adjuvant. We demonstrate, for the first time, proteasome-dependent and independent cross-presentation of HLA-A-, B-, and C-restricted epitopes within the same full-length tumor antigen by human DCs. Our findings identify important differences in the capacities of human DC subsets to cross-present clinically relevant, full-length tumor antigens and how vaccine formulation impacts CTL responses in vivo.
authors.affiliation: Ludwig Institute for Cancer Research, Centre for Clinical Sciences, Austin Health, Melbourne, VIC 3084, Australia. neil.robson@ed.ac.uk
authors.forename: Neil C
authors.initials: NC
authors.lastname: Robson
authors.forename: Tristan
authors.initials: T
authors.lastname: McAlpine
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Knights
authors.forename: Max
authors.initials: M
authors.lastname: Schnurr
authors.forename: Amanda
authors.initials: A
authors.lastname: Shin
authors.forename: Weisan
authors.initials: W
authors.lastname: Chen
authors.forename: Eugene
authors.initials: E
authors.lastname: Maraskovsky
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cebon
mesh_terms: D017951:Antigen Presentation / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology; D002784:Cholesterol / Q000276:immunology; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D004338:Drug Combinations; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015234:HLA-A Antigens / Q000276:immunology; D015235:HLA-B Antigens / Q000276:immunology; D015236:HLA-C Antigens / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D058965:MART-1 Antigen; D009363:Neoplasm Proteins / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology*; D010743:Phospholipids / Q000276:immunology; D046988:Proteasome Endopeptidase Complex / Q000276:immunology; D012503:Saponins / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D004338:Drug Combinations; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015236:HLA-C Antigens; D015395:Histocompatibility Antigens Class I; C493786:ISCOMATRIX; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D010743:Phospholipids; D012503:Saponins; C504237:peptide NY-ESO-1 157-165; D002784:Cholesterol; D046988:Proteasome Endopeptidase Complex