title: The antigenic landscape of multiple myeloma: mass spectrometry (re)defines targets for T-cell-based immunotherapy.
abstract: Direct analysis of HLA-presented antigens by mass spectrometry provides a comprehensive view on the antigenic landscape of different tissues/malignancies and enables the identification of novel, pathophysiologically relevant T-cell epitopes. Here, we present a systematic and comparative study of the HLA class I and II presented, nonmutant antigenome of multiple myeloma (MM). Quantification of HLA surface expression revealed elevated HLA molecule counts on malignant plasma cells compared with normal B cells, excluding relevant HLA downregulation in MM. Analyzing the presentation of established myeloma-associated T-cell antigens on the HLA ligandome level, we found a substantial proportion of antigens to be only infrequently presented on primary myelomas or to display suboptimal degrees of myeloma specificity. However, unsupervised analysis of our extensive HLA ligand data set delineated a panel of 58 highly specific myeloma-associated antigens (including multiple myeloma SET domain containing protein) which are characterized by frequent and exclusive presentation on myeloma samples. Functional characterization of these target antigens revealed peptide-specific, preexisting CD8(+) T-cell responses exclusively in myeloma patients, which is indicative of pathophysiological relevance. Furthermore, in vitro priming experiments revealed that peptide-specific T-cell responses can be induced in response-naive myeloma patients. Together, our results serve to guide antigen selection for T-cell-based immunotherapy of MM.
authors.affiliation: Department of Hematology and Oncology, Institute for Cell Biology, Department of Immunology, and.
authors.forename: Simon
authors.initials: S
authors.lastname: Walz
authors.affiliation: Department of Hematology and Oncology.
authors.forename: Juliane S
authors.initials: JS
authors.lastname: Stickel
authors.affiliation: Institute for Cell Biology, Department of Immunology, and.
authors.forename: Daniel Johannes
authors.initials: DJ
authors.lastname: Kowalewski
authors.affiliation: Institute for Cell Biology, Department of Immunology, and.
authors.forename: Heiko
authors.initials: H
authors.lastname: Schuster
authors.affiliation: Department of Hematology and Oncology.
authors.forename: Katja
authors.initials: K
authors.lastname: Weisel
authors.affiliation: Institute for Cell Biology, Department of Immunology, and Applied Bioinformatics, Center for Bioinformatics and Department of Computer Science, University of Tübingen, Tübingen, Germany;
authors.forename: Linus
authors.initials: L
authors.lastname: Backert
authors.affiliation: Institute for Cell Biology, Department of Immunology, and.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kahn
authors.affiliation: Institute for Cell Biology, Department of Immunology, and.
authors.forename: Annika
authors.initials: A
authors.lastname: Nelde
authors.affiliation: Institute for Cell Biology, Department of Immunology, and.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Stroh
authors.affiliation: Department of Orthopedics, Hospital Group South-West, Calw, Germany; and.
authors.forename: Martin
authors.initials: M
authors.lastname: Handel
authors.affiliation: Applied Bioinformatics, Center for Bioinformatics and Department of Computer Science, University of Tübingen, Tübingen, Germany;
authors.forename: Oliver
authors.initials: O
authors.lastname: Kohlbacher
authors.affiliation: Department of Hematology and Oncology.
authors.forename: Lothar
authors.initials: L
authors.lastname: Kanz
authors.affiliation: Department of Hematology and Oncology, Clinical Cooperation Unit Translational Immunology and.
authors.forename: Helmut Rainer
authors.initials: HR
authors.lastname: Salih
authors.affiliation: Institute for Cell Biology, Department of Immunology, and Cancer Immunotherapy Unit, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Rammensee
authors.affiliation: Institute for Cell Biology, Department of Immunology, and Cancer Immunotherapy Unit, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Stevanović
mesh_terms: D000328:Adult; D000368:Aged; D017951:Antigen Presentation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000276:immunology*; D053719:Tandem Mass Spectrometry
chemical_list: D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II