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Immune Surveillance of Acute Myeloid Leukemia Is Mediated by HLA-Presented Antigens on Leukemia Progenitor Cells. 2023
Annika Nelde, and
Heiko Schuster, and
Jonas S Heitmann, and
Jens Bauer, and
Yacine Maringer, and
Melissa Zwick, and
Jens-Peter Volkmer, and
James Y Chen, and
Anna M Paczulla Stanger, and
Ariane Lehmann, and
Bismark Appiah, and
Melanie Märklin, and
Elke Rücker-Braun, and
Helmut R Salih, and
Malte Roerden, and
Sarah M Schroeder, and
Max-Felix Häring, and
Andreas Schlosser, and
Johannes Schetelig, and
Marc Schmitz, and
Melanie Boerries, and
Natalie Köhler, and
Claudia Lengerke, and
Ravindra Majeti, and
Irving L Weissman, and
Hans-Georg Rammensee, and
Juliane S Walz
Department of Peptide-Based Immunotherapy, University and University Hospital Tübingen, Tübingen, Germany.
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. 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. 430 . This article is featured in Selected Articles from This Issue, p. 419.
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