title: HLA ligandome analysis identifies the underlying specificities of spontaneous antileukemia immune responses in chronic lymphocytic leukemia (CLL).
abstract: The breakthrough development of clinically effective immune checkpoint inhibitors illustrates the potential of T-cell-based immunotherapy to effectively treat malignancies. A remaining challenge is to increase and guide the specificities of anticancer immune responses, e.g., by therapeutic vaccination or by adoptive T-cell transfer. By analyzing the landscape of naturally presented HLA class I and II ligands of primary chronic lymphocytic leukemia (CLL), we delineated a novel category of tumor-associated T-cell antigens based on their exclusive and frequent representation in the HLA ligandome of leukemic cells. These antigens were validated across different stages and mutational subtypes of CLL and found to be robustly represented in HLA ligandomes of patients undergoing standard chemo-/immunotherapy. We demonstrate specific immune recognition of these antigens exclusively in CLL patients, with the frequencies of representation in CLL ligandomes correlating with the frequencies of immune recognition by patient T cells. Moreover, retrospective survival analysis revealed survival benefits for patients displaying immune responses to these antigens. These results directly imply these nonmutant self-peptides as pathophysiologically relevant tumor antigens and encourages their implementation for cancer immunotherapy.
authors.affiliation: Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen 72076, Germany;
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Kowalewski
authors.affiliation: Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen 72076, Germany;
authors.forename: Heiko
authors.initials: H
authors.lastname: Schuster
authors.affiliation: Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen 72076, Germany; Applied Bioinformatics, Center for Bioinformatics and Department of Computer Science, University of Tübingen, Tübingen 72076, Germany;
authors.forename: Linus
authors.initials: L
authors.lastname: Backert
authors.affiliation: Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen 72076, Germany; Department of Hematology and Oncology, University of Tübingen, Tübingen 72076, Germany;
authors.forename: Claudia
authors.initials: C
authors.lastname: Berlin
authors.affiliation: Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen 72076, Germany;
authors.forename: Stefan
authors.initials: S
authors.lastname: Kahn
authors.affiliation: Department of Hematology and Oncology, University of Tübingen, Tübingen 72076, Germany;
authors.forename: Lothar
authors.initials: L
authors.lastname: Kanz
authors.affiliation: Department of Hematology and Oncology, University of Tübingen, Tübingen 72076, Germany; Clinical Cooperation Unit Translational Immunology, DKFZ Partner Site Tübingen, German Cancer Consortium (DKTK), Tübingen 72076, Germany; and.
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Salih
authors.affiliation: Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen 72076, Germany; DKFZ Partner Site Tübingen, German Cancer Consortium (DKTK), Tübingen 72076, Germany.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Rammensee
authors.affiliation: Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen 72076, Germany; DKFZ Partner Site Tübingen, German Cancer Consortium (DKTK), Tübingen 72076, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Stevanovic
authors.affiliation: Department of Hematology and Oncology, University of Tübingen, Tübingen 72076, Germany; juliane.stickel@med.uni-tuebingen.de.
authors.forename: Juliane Sarah
authors.initials: JS
authors.lastname: Stickel
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D017951:Antigen Presentation; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology; D005260:Female; D006680:HLA Antigens / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D007167:Immunotherapy / Q000379:methods*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000628:therapy*; D008024:Ligands; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D022223:Vaccines, Subunit / Q000235:genetics / Q000276:immunology
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D006680:HLA Antigens; D008024:Ligands; D022223:Vaccines, Subunit
keywords: HLA; cancer immunotherapy; chronic lymphocytic leukemia; therapeutic vaccination; tumor-associated antigens