title: Dendritic cells loaded with mRNA encoding full-length tumor antigens prime CD4+ and CD8+ T cells in melanoma patients.
abstract: It is generally thought that dendritic cells (DCs) loaded with full-length tumor antigen could improve immunotherapy by stimulating broad T-cell responses and by allowing treatment irrespective of the patient's human leukocyte antigen (HLA) type. To investigate this, we determined the specificity of T cells from melanoma patients treated with DCs loaded with mRNA encoding a full-length tumor antigen fused to a signal peptide and an HLA class II sorting signal, allowing presentation in HLA class I and II. In delayed-type hypersensitive (DTH)-biopsies and blood, we found functional CD8(+) and CD4(+) T cells recognizing novel treatment-antigen-derived epitopes, presented by several HLA types. Additionally, we identified a CD8(+) response specific for the signal peptide incorporated to elicit presentation by HLA class II and a CD4(+) response specific for the fusion region of the signal peptide and one of the antigens. This demonstrates that the fusion proteins contain newly created immunogenic sequences and provides evidence that ex vivo-generated mRNA-modified DCs can induce effector CD8(+) and CD4(+) T cells from the naive T-cell repertoire of melanoma patients. Thus, this work provides definitive proof that DCs presenting the full antigenic spectrum of tumor antigens can induce T cells specific for novel epitopes and can be administered to patients irrespective of their HLA type.
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Immunology-Physiology, Medical School of the Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: An M T
authors.initials: AM
authors.lastname: Van Nuffel
authors.forename: Daphné
authors.initials: D
authors.lastname: Benteyn
authors.forename: Sofie
authors.initials: S
authors.lastname: Wilgenhof
authors.forename: Lauranne
authors.initials: L
authors.lastname: Pierret
authors.forename: Jurgen
authors.initials: J
authors.lastname: Corthals
authors.forename: Carlo
authors.initials: C
authors.lastname: Heirman
authors.forename: Pierre
authors.initials: P
authors.lastname: van der Bruggen
authors.forename: Pierre G
authors.initials: PG
authors.lastname: Coulie
authors.forename: Bart
authors.initials: B
authors.lastname: Neyns
authors.forename: Kris
authors.initials: K
authors.lastname: Thielemans
authors.forename: Aude
authors.initials: A
authors.lastname: Bonehill
mesh_terms: D000595:Amino Acid Sequence; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation*; D018274:Electroporation; D006681:HLA-D Antigens / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008969:Molecular Sequence Data; D021382:Protein Sorting Signals; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology*; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D014162:Transfection
chemical_list: D000951:Antigens, Neoplasm; D006681:HLA-D Antigens; D015395:Histocompatibility Antigens Class I; D021382:Protein Sorting Signals; D012333:RNA, Messenger