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Tatjana Bilich, Annika Nelde, Leon B, Malte Roerden, Helmut R Salih, Daniel J Kowalewski, Heiko Schuster, Chih-Chiang Tsou, Ana Marcu, Marian C Neidert, Maren Lübke, Jonas Rieth, Mirle Schemionek, Tim H Brümmendorf, Vladan Vucinic, Dietger Niederwieser, Jens Bauer, Melanie Märklin, Janet K Peper, Reinhild Klein, Lothar Kanz, Hans-Georg Rammensee, Stefan Stevanovic, and Juliane S Walz (accepted)

The HLA ligandome landscape of chronic myeloid leukemia delineates novel T-cell epitopes for immunotherapy

Blood.

Anti-leukemia immunity plays an important role in disease control and maintenance of tyrosine kinase inhibitor (TKI)-free remission in chronic myeloid leukemia (CML). Thus, antigen-specific immunotherapy holds promise to strengthen immune control in CML, but requires the identification of CML-associated targets. In this study, we used a mass spectrometry-based approach to identify naturally presented, HLA class I- and class II-restricted peptides in primary CML samples. Comparative HLA ligandome profiling using a comprehensive dataset of different hematological benign specimen and samples of CML patients in deep molecular remission delineated a panel of novel, frequently presented, CML-exclusive peptides. These non-mutated target antigens are of particular relevance since our extensive data mining approach suggests absence of naturally presented, BCR-ABL- and ABL-BCR-derived, HLA-restricted peptides and lack of frequent, tumor-exclusive presentation of known cancer/testis and leukemia-associated antigens. Functional characterization revealed spontaneous T-cell responses against the newly identified CML-associated peptides in CML patient samples and their ability to induce multifunctional and cytotoxic antigen-specific T cells de novo in samples of healthy volunteers and CML patients. These antigens are thus prime candidates for T cell-based immunotherapeutic approaches that may prolong TKI-free survival and even mediate cure of CML patients.
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30530751
10.1182/blood-2018-07-866830