Bilich and Nelde et al. performed mass spectrometry-based HLA ligandome analysis of PBMCs from primary chronic myeloid leukemia (CML) in comparison to normal hematological tissues or CML patients in deep molecular remission to reveal a panel of novel, non-mutated, CML-associated target epitopes. Limited pre-existing epitope-specific T cells were observed in CML patients, but in vitro priming resulted in multifunctional, cytotoxic, peptide-specific CD8+ T cells for most tested epitopes in both healthy volunteer and CML patient samples. Viral epitope-specific CD8+ T cells in patients being treated with TKIs showed reduced functionality.

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.

Author Info: (1) Institute for Cell Biology, Department of Immunology, University of Tuebingen, Germany. (2) Department of Hematology and Oncology, University Hospital Tuebingen, Germany. (3) Applied Bioinformatics

Author Info: (1) Institute for Cell Biology, Department of Immunology, University of Tuebingen, Germany. (2) Department of Hematology and Oncology, University Hospital Tuebingen, Germany. (3) Applied Bioinformatics, Center for Bioinformatics and Department of Computer Science, University of Tuebingen, Germany. (4) Department of Hematology and Oncology, University Hospital Tuebingen, Germany. (5) Clinical Cooperation Unit Translational Immunology, German Cancer Consortium (DKTK), DKFZ partner site Tuebingen, Germany. (6) Immatics Biotechnologies GmbH, Tuebingen, Germany. (7) Immatics Biotechnologies GmbH, Tuebingen, Germany. (8) Immatics US, Houston, TX, United States. (9) Institute for Cell Biology, Department of Immunology, University of Tuebingen, Germany. (10) Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, Switzerland. (11) Institute for Cell Biology, Department of Immunology, University of Tuebingen, Germany. (12) Institute for Cell Biology, Department of Immunology, University of Tuebingen, Germany. (13) Department of Hematology, Oncology, Hemostaseology, and SCT, University Hospital RWTH Aachen, Germany. (14) Department of Hematology, Oncology, Hemostaseology, and SCT, University Hospital RWTH Aachen, Germany. (15) Department of Hematology and Oncology, University Hospital Leipzig, Germany. (16) Department of Hematology and Oncology, University Hospital Leipzig, Germany. (17) Institute for Cell Biology, Department of Immunology, University of Tuebingen, Germany. (18) Clinical Cooperation Unit Translational Immunology, German Cancer Consortium (DKTK), DKFZ partner site Tuebingen, Germany. (19) Institute for Cell Biology, Department of Immunology, University of Tuebingen, Germany. (20) Department of Hematology and Oncology, University Hospital Tuebingen, Germany. (21) Quantitative Biology Center, University of Tuebingen, Germany. (22) Department of Hematology and Oncology, University Hospital Tuebingen, Germany. (23) German Cancer Consortium (DKTK), DKFZ partner site Tuebingen, Germany. (24) Institute for Cell Biology, Department of Immunology, University of Tuebingen, Germany. (25) Department of Hematology and Oncology, University Hospital Tuebingen, Germany; juliane.walz@med.uni-tuebingen.de.

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