Immune Surveillance of Acute Myeloid Leukemia Is Mediated by HLA-Presented Antigens on Leukemia Progenitor Cells

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Annika Nelde - , University Hospital Tübingen (Author)
  • Heiko Schuster - , University Hospital Tübingen (Author)
  • Jonas S Heitmann - , University Hospital Tübingen (Author)
  • Jens Bauer - , University Hospital Tübingen (Author)
  • Yacine Maringer - , University Hospital Tübingen (Author)
  • Melissa Zwick - , University of Freiburg (Author)
  • Jens-Peter Volkmer - , Stanford Medicine (Author)
  • James Y Chen - , Stanford Medicine (Author)
  • Anna M Paczulla Stanger - , University Hospital Tübingen (Author)
  • Ariane Lehmann - , University of Freiburg (Author)
  • Bismark Appiah - , University of Freiburg (Author)
  • Melanie Märklin - , University Hospital Tübingen (Author)
  • Elke Rücker-Braun - , Department of internal Medicine I, Center for Regenerative Therapies Dresden (Author)
  • Helmut R Salih - , University Hospital Tübingen (Author)
  • Malte Roerden - , University Hospital Tübingen (Author)
  • Sarah M Schroeder - , University Hospital Tübingen (Author)
  • Max-Felix Häring - , University Hospital Tübingen (Author)
  • Andreas Schlosser - , University Hospital of Würzburg (Author)
  • Johannes Schetelig - , Department of internal Medicine I, DKMS Donor Center gGmbH (Author)
  • Marc Schmitz - , Institute for Immunology, National Center for Tumor Diseases (Partners: UKD, MFD, HZDR, DKFZ), German Cancer Consortium (Partner: DKTK, DKFZ), German Center for Neurodegenerative Diseases, Dresden site (Partner: DZNE of the Helmholtz Association), University Hospital Carl Gustav Carus Dresden, German Cancer Research Center (DKFZ) (Author)
  • Melanie Boerries - , University of Freiburg (Author)
  • Natalie Köhler - , University of Freiburg (Author)
  • Claudia Lengerke - , University Hospital Tübingen (Author)
  • Ravindra Majeti - , Stanford Medicine (Author)
  • Irving L Weissman - , Stanford Medicine (Author)
  • Hans-Georg Rammensee - , University Hospital Tübingen (Author)
  • Juliane S Walz - , University Hospital Tübingen (Author)

Abstract

UNLABELLED: 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. 430 . This article is featured in Selected Articles from This Issue, p. 419.

Details

Original languageEnglish
Pages (from-to)468-489
Number of pages22
JournalBlood cancer discovery
Volume4
Issue number6
Publication statusPublished - 1 Nov 2023
Peer-reviewedYes

External IDs

PubMedCentral PMC10618727
unpaywall 10.1158/2643-3230.bcd-23-0020
Scopus 85177494937

Keywords

Keywords

  • Humans, HLA Antigens, Leukemia, Myeloid, Acute/genetics, Peptides, Stem Cells