The antigenic landscape of multiple myeloma: mass spectrometry (re)defines targets for T-cell-based immunotherapy
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The antigenic landscape of multiple myeloma: mass spectrometry (re)defines targets for T-cell-based immunotherapy. / Walz, Simon; Stickel, Juliane S; Kowalewski, Daniel Johannes; Schuster, Heiko; Weisel, Katja; Backert, Linus; Kahn, Stefan; Nelde, Annika; Stroh, Tatjana; Handel, Martin; Kohlbacher, Oliver; Kanz, Lothar; Salih, Helmut Rainer; Rammensee, Hans-Georg; Stevanović, Stefan.
in: BLOOD, Jahrgang 126, Nr. 10, 03.09.2015, S. 1203-13.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - The antigenic landscape of multiple myeloma: mass spectrometry (re)defines targets for T-cell-based immunotherapy
AU - Walz, Simon
AU - Stickel, Juliane S
AU - Kowalewski, Daniel Johannes
AU - Schuster, Heiko
AU - Weisel, Katja
AU - Backert, Linus
AU - Kahn, Stefan
AU - Nelde, Annika
AU - Stroh, Tatjana
AU - Handel, Martin
AU - Kohlbacher, Oliver
AU - Kanz, Lothar
AU - Salih, Helmut Rainer
AU - Rammensee, Hans-Georg
AU - Stevanović, Stefan
N1 - © 2015 by The American Society of Hematology.
PY - 2015/9/3
Y1 - 2015/9/3
N2 - 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.
AB - 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.
KW - Adult
KW - Aged
KW - Antigen Presentation
KW - Antigens, Neoplasm
KW - CD8-Positive T-Lymphocytes
KW - Epitopes, T-Lymphocyte
KW - Female
KW - Histocompatibility Antigens Class I
KW - Histocompatibility Antigens Class II
KW - Humans
KW - Immunotherapy
KW - Lymphocyte Activation
KW - Male
KW - Middle Aged
KW - Multiple Myeloma
KW - Tandem Mass Spectrometry
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1182/blood-2015-04-640532
DO - 10.1182/blood-2015-04-640532
M3 - SCORING: Journal article
C2 - 26138685
VL - 126
SP - 1203
EP - 1213
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 10
ER -