title: Carfilzomib alters the HLA-presented peptidome of myeloma cells and impairs presentation of peptides with aromatic C-termini.
abstract: Recent studies suggest that multiple myeloma is an immunogenic disease, which might be effectively targeted by antigen-specific T-cell immunotherapy. As standard of care in myeloma includes proteasome inhibitor therapy, it is of great importance to characterize the effects of this treatment on HLA-restricted antigen presentation and implement only robustly presented targets for immunotherapeutic intervention. Here, we present a study that longitudinally and semi-quantitatively maps the effects of the proteasome inhibitor carfilzomib on HLA-restricted antigen presentation. The relative presentation levels of 4780 different HLA ligands were quantified in an in vitro model employing carfilzomib treatment of MM.1S and U266 myeloma cells, which revealed significant modulation of a substantial fraction of the HLA-presented peptidome. Strikingly, we detected selective down-modulation of HLA ligands with aromatic C-terminal anchor amino acids. This particularly manifested as a marked reduction in the presentation of HLA ligands through the HLA allotypes A*23:01 and A*24:02 on MM.1S cells. These findings implicate that carfilzomib mediates a direct, peptide motif-specific inhibitory effect on HLA ligand processing and presentation. As a substantial proportion of HLA allotypes present peptides with aromatic C-termini, our results may have broad implications for the implementation of antigen-specific treatment approaches in patients undergoing carfilzomib treatment.
authors.affiliation: Department of Immunology, Institute for Cell Biology, University of Tübingen, Tübingen, Germany.
authors.forename: D J
authors.initials: DJ
authors.lastname: Kowalewski
authors.affiliation: Department of Immunology, Institute for Cell Biology, University of Tübingen, Tübingen, Germany.|Department of Hematology and Oncology, University of Tübingen, Tübingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Walz
authors.affiliation: Department of Immunology, Institute for Cell Biology, University of Tübingen, Tübingen, Germany.|Applied Bioinformatics, Department of Computer Science, Center for Bioinformatics, University of Tübingen, Tübingen, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Backert
authors.affiliation: Department of Immunology, Institute for Cell Biology, University of Tübingen, Tübingen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Schuster
authors.affiliation: Applied Bioinformatics, Department of Computer Science, Center for Bioinformatics, University of Tübingen, Tübingen, Germany.|Quantitative Biology Center, University of Tübingen, Tübingen, Germany.|Max Planck Institute for Developmental Biology, Tübingen, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Kohlbacher
authors.affiliation: Department of Hematology and Oncology, University of Tübingen, Tübingen, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Weisel
authors.affiliation: Department of Hematology and Oncology, University of Tübingen, Tübingen, Germany.
authors.forename: S M
authors.initials: SM
authors.lastname: Rittig
authors.affiliation: Department of Hematology and Oncology, University of Tübingen, Tübingen, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Kanz
authors.affiliation: Department of Hematology and Oncology, University of Tübingen, Tübingen, Germany.|Clinical Cooperation Unit Translational Immunology, German Cancer Consortium (DKTK), DKFZ Partner Site, Tübingen, Germany.
authors.forename: H R
authors.initials: HR
authors.lastname: Salih
authors.affiliation: Department of Immunology, Institute for Cell Biology, University of Tübingen, Tübingen, Germany.|German Cancer Consortium (DKTK), DKFZ Partner Site, Tübingen, Germany.
authors.forename: H-G
authors.initials: HG
authors.lastname: Rammensee
authors.affiliation: Department of Immunology, Institute for Cell Biology, University of Tübingen, Tübingen, Germany.|German Cancer Consortium (DKTK), DKFZ Partner Site, Tübingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Stevanović
authors.affiliation: Department of Hematology and Oncology, University of Tübingen, Tübingen, Germany.
authors.forename: J S
authors.initials: JS
authors.lastname: Stickel
mesh_terms: D017951:Antigen Presentation / Q000187:drug effects* / Q000276:immunology*; D015415:Biomarkers; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D000939:Epitopes / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D006680:HLA Antigens / Q000276:immunology* / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D008024:Ligands; D013058:Mass Spectrometry; D009101:Multiple Myeloma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D009842:Oligopeptides / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D015415:Biomarkers; D000939:Epitopes; D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D008024:Ligands; D009842:Oligopeptides; D010455:Peptides; D061988:Proteasome Inhibitors; C524865:carfilzomib