title: Therapeutic targeting of naturally presented myeloperoxidase-derived HLA peptide ligands on myeloid leukemia cells by TCR-transgenic T cells.
abstract: T cells have been proven to be therapeutically effective in patients with relapsed leukemias, although target antigens on leukemic cells as well as T-cell receptors (TCRs), potentially recognizing those antigens, are mostly unknown. We have applied an immunopeptidomic approach and isolated human leukocyte antigen (HLA) ligands from primary leukemia cells. We identified a number of ligands derived from different genes that are restrictedly expressed in the hematopoietic system. We exemplarily selected myeloperoxidase (MPO) as a potential target and isolated a high-avidity TCR with specificity for a HLA-B*07:02-(HLA-B7)-restricted epitope of MPO in the single HLA-mismatched setting. T cells transgenic for this TCR demonstrated high peptide and antigen specificity as well as leukemia reactivity in vitro and in vivo. In contrast, no significant on- and off-target toxicity could be observed. In conclusion, we here demonstrate, exemplarily for MPO, that leukemia-derived HLA ligands can be selected for specific effector tool development to redirect T cells to be used for graft manipulation or adoptive T-cell therapies in diverse transplant settings. This approach can be extended to other HLA ligands and HLA molecules in order to provide better treatment options for this life-threatening disease.
authors.affiliation: Medizinische Klinik III, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Klar
authors.affiliation: Medizinische Klinik III, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schober
authors.affiliation: Medizinische Klinik III, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Rami
authors.affiliation: Medizinische Klinik III, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Mall
authors.affiliation: Research Unit Protein Science, Helmholtz Zentrum München (GmbH), German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Merl
authors.affiliation: Research Unit Protein Science, Helmholtz Zentrum München (GmbH), German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: S M
authors.initials: SM
authors.lastname: Hauck
authors.affiliation: Research Unit Protein Science, Helmholtz Zentrum München (GmbH), German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Ueffing
authors.affiliation: Department of Biology, Technion Israel Institute of Technology, Haifa, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Admon
authors.affiliation: Institut für Allgemeine Pathologie und Pathologische Anatomie, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Slotta-Huspenina
authors.affiliation: Nuklearmedizinische Klinik, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schwaiger
authors.affiliation: Department of Immunology, University of Tübingen, Tübingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Stevanović
authors.affiliation: Medizinische Klinik III, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: R A J
authors.initials: RA
authors.lastname: Oostendorp
authors.affiliation: 1] Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, München, Germany [2] Clinical Cooperation Group, Antigen Specific T Cell Therapy, Helmholtz Zentrum München (GmbH), German Center for Environmental Health, München, Germany.
authors.forename: D H
authors.initials: DH
authors.lastname: Busch
authors.affiliation: 1] Medizinische Klinik III, Klinikum rechts der Isar, Technische Universität München, München, Germany [2] German Cancer Consortium (DKTK), Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Peschel
authors.affiliation: 1] Medizinische Klinik III, Klinikum rechts der Isar, Technische Universität München, München, Germany [2] Clinical Cooperation Group, Antigen Specific T Cell Therapy, Helmholtz Zentrum München (GmbH), German Center for Environmental Health, München, Germany [3] German Cancer Consortium (DKTK), Munich, Germany.
authors.forename: A M
authors.initials: AM
authors.lastname: Krackhardt
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology; D006680:HLA Antigens / Q000276:immunology* / Q000378:metabolism; D015793:HLA-B7 Antigen / Q000276:immunology / Q000378:metabolism; D064593:Heterografts; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000401:mortality; D008024:Ligands; D051379:Mice; D010455:Peptides / Q000276:immunology* / Q000378:metabolism; D009195:Peroxidase / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000378:metabolism; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D014161:Transduction, Genetic
chemical_list: D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; C425023:HLA-B*07 antigen; D015793:HLA-B7 Antigen; D015395:Histocompatibility Antigens Class I; D008024:Ligands; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D009195:Peroxidase
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