Using mass spectrometry-based immunopeptidomics, Nelde et al. characterized bulk AML cells and leukemia stem and progenitor cells (LSCs; often responsible for AML relapse), and found that they presented similar, but not identical, HLA-I- and HLA-II-restricted antigens. These antigens included non-mutated peptides, cryptic neoepitopes, and neoepitopes of common AML driver mutations of NPM1 and IDH2. In patient samples, pre-existing memory T cells were identified, and de novo T cell responses could be induced. In patient data, pre-existing memory responses and high HLA-II immunopeptidome diversity correlated with positive clinical outcomes.
Contributed by Lauren Hitchings
ABSTRACT: Therapy-resistant leukemia stem and progenitor cells (LSC) are a main cause of acute myeloid leukemia (AML) relapse. LSC-targeting therapies may thus improve outcome of patients with AML. Here we demonstrate that LSCs present HLA-restricted antigens that induce T-cell responses allowing for immune surveillance of AML. Using a mass spectrometry-based immunopeptidomics approach, we characterized the antigenic landscape of patient LSCs and identified AML- and AML/LSC-associated HLA-presented antigens absent from normal tissues comprising nonmutated peptides, cryptic neoepitopes, and neoepitopes of common AML driver mutations of NPM1 and IDH2. Functional relevance of shared AML/LSC antigens is illustrated by presence of their cognizant memory T cells in patients. Antigen-specific T-cell recognition and HLA class II immunopeptidome diversity correlated with clinical outcome. Together, these antigens shared among AML and LSCs represent prime targets for T cell-based therapies with potential of eliminating residual LSCs in patients with AML. SIGNIFICANCE: The elimination of therapy-resistant leukemia stem and progenitor cells (LSC) remains a major challenge in the treatment of AML. This study identifies and functionally validates LSC-associated HLA class I and HLA class II-presented antigens, paving the way to the development of LSC-directed T cell-based immunotherapeutic approaches for patients with AML. See related commentary by Ritz, p. 437 .
Author Info: (1) Department of Peptide-Based Immunotherapy, University and University Hospital Tbingen, Tbingen, Germany. Institute for Cell Biology, Department of Immunology, University of T
Author Info: (1) Department of Peptide-Based Immunotherapy, University and University Hospital Tbingen, Tbingen, Germany. Institute for Cell Biology, Department of Immunology, University of Tbingen, Tbingen, Germany. Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tbingen, Tbingen, Germany. (2) Institute for Cell Biology, Department of Immunology, University of Tbingen, Tbingen, Germany. (3) Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tbingen, Tbingen, Germany. Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tbingen, Tbingen, Germany. (4) Department of Peptide-Based Immunotherapy, University and University Hospital Tbingen, Tbingen, Germany. Institute for Cell Biology, Department of Immunology, University of Tbingen, Tbingen, Germany. Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tbingen, Tbingen, Germany. (5) Department of Peptide-Based Immunotherapy, University and University Hospital Tbingen, Tbingen, Germany. Institute for Cell Biology, Department of Immunology, University of Tbingen, Tbingen, Germany. Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tbingen, Tbingen, Germany. (6) Department of Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany. (7) Institute for Stem Cell Biology and Regenerative Medicine and the Ludwig Cancer Center, Stanford University School of Medicine, Stanford, California. (8) Institute for Stem Cell Biology and Regenerative Medicine and the Ludwig Cancer Center, Stanford University School of Medicine, Stanford, California. (9) Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tbingen, Tbingen, Germany. Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland. (10) Faculty of Medicine, Medical Center, Institute of Medical Bioinformatics and Systems Medicine (IBSM), University of Freiburg, Germany. (11) Faculty of Medicine, Medical Center, Institute of Medical Bioinformatics and Systems Medicine (IBSM), University of Freiburg, Germany. (12) Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tbingen, Tbingen, Germany. Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tbingen, Tbingen, Germany. (13) Department of Medicine I, University Hospital of Dresden, Dresden, Germany. Center for Regenerative Therapies Dresden, Technische Universitt Dresden, Dresden, Germany. (14) Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tbingen, Tbingen, Germany. Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tbingen, Tbingen, Germany. (15) Department of Peptide-Based Immunotherapy, University and University Hospital Tbingen, Tbingen, Germany. Institute for Cell Biology, Department of Immunology, University of Tbingen, Tbingen, Germany. Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tbingen, Tbingen, Germany. (16) Department of Peptide-Based Immunotherapy, University and University Hospital Tbingen, Tbingen, Germany. Institute for Cell Biology, Department of Immunology, University of Tbingen, Tbingen, Germany. Department of Otorhinolaryngology, Head and Neck Surgery, University of Tbingen, Tbingen, Germany. (17) Department of Peptide-Based Immunotherapy, University and University Hospital Tbingen, Tbingen, Germany. Institute for Cell Biology, Department of Immunology, University of Tbingen, Tbingen, Germany. Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tbingen, Tbingen, Germany. (18) Rudolf-Virchow-Zentrum, University Wrzburg, Wrzburg, Germany. (19) Department of Medicine I, University Hospital of Dresden, Dresden, Germany. German Bone Marrow Donor Center (DKMS), Clinical Trials Unit, Dresden, Germany. (20) Institute of Immunology, Faculty of Medicine Carl Gustav Carus, Technische Universitt Dresden, Dresden, Germany. National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, Technische Universitt Dresden, Dresden, Germany. German Cancer Consortium (DKTK), partner site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany. (21) Faculty of Medicine, Medical Center, Institute of Medical Bioinformatics and Systems Medicine (IBSM), University of Freiburg, Germany. Comprehensive Cancer Center Freiburg (CCCF), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany. German Cancer Consortium (DKTK), Partner Site, Freiburg, and German Cancer Research Center (DKFZ), Heidelberg, Germany. (22) Department of Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Centre for Integrative Biological Signalling Studies (CIBSS), University of Freiburg, Freiburg, Germany. (23) Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tbingen, Tbingen, Germany. Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland. Clinic for Hematology, University of Basel and University Hospital Basel, Basel, Switzerland. German Cancer Consortium (DKTK), DKFZ partner site Tbingen, Germany. (24) Institute for Stem Cell Biology and Regenerative Medicine and the Ludwig Cancer Center, Stanford University School of Medicine, Stanford, California. Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, California. (25) Institute for Stem Cell Biology and Regenerative Medicine and the Ludwig Cancer Center, Stanford University School of Medicine, Stanford, California. (26) Institute for Cell Biology, Department of Immunology, University of Tbingen, Tbingen, Germany. Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tbingen, Tbingen, Germany. German Cancer Consortium (DKTK), DKFZ partner site Tbingen, Germany. (27) Department of Peptide-Based Immunotherapy, University and University Hospital Tbingen, Tbingen, Germany. Institute for Cell Biology, Department of Immunology, University of Tbingen, Tbingen, Germany. Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tbingen, Tbingen, Germany. Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tbingen, Tbingen, Germany.
