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Immune Surveillance of Acute Myeloid Leukemia Is Mediated by HLA-Presented Antigens on Leukemia Progenitor Cells. Blood cancer discovery Nelde, A., Schuster, H., Heitmann, J. S., Bauer, J., Maringer, Y., Zwick, M., Volkmer, J. P., Chen, J. Y., Stanger, A. M., Lehmann, A., Appiah, B., Märklin, M., Rücker-Braun, E., Salih, H. R., Roerden, M., Schroeder, S. M., Häring, M. F., Schlosser, A., Schetelig, J., Schmitz, M., Boerries, M., Köhler, N., Lengerke, C., Majeti, R., Weissman, I. L., Rammensee, H. G., Walz, J. S. 2023: OF1-OF22

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.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 .

View details for DOI 10.1158/2643-3230.BCD-23-0020

View details for PubMedID 37847741