Immune Surveillance of Acute Myeloid Leukemia Is Mediated by HLA-Presented Antigens on Leukemia Progenitor Cells-Reference-Cited by-同舟云学术

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

Published:2023-10-17 Issue:6 Volume:4 Page:468-489
ISSN:2643-3230
Container-title:Blood Cancer Discovery
language:en
Short-container-title:

Author:

Nelde Annika¹²³^ORCID,Schuster Heiko²^ORCID,Heitmann Jonas S.³⁴^ORCID,Bauer Jens¹²³^ORCID,Maringer Yacine¹²³^ORCID,Zwick Melissa⁵^ORCID,Volkmer Jens-Peter⁶,Chen James Y.⁶^ORCID,Stanger Anna M. Paczulla⁷⁸^ORCID,Lehmann Ariane⁹^ORCID,Appiah Bismark⁹^ORCID,Märklin Melanie³⁴^ORCID,Rücker-Braun Elke¹⁰¹¹^ORCID,Salih Helmut R.³⁴^ORCID,Roerden Malte¹²⁷^ORCID,Schroeder Sarah M.¹²¹²^ORCID,Häring Max-Felix¹²⁷,Schlosser Andreas¹³^ORCID,Schetelig Johannes¹⁰¹⁴^ORCID,Schmitz Marc¹⁵¹⁶¹⁷^ORCID,Boerries Melanie⁹¹⁸¹⁹^ORCID,Köhler Natalie⁵²⁰^ORCID,Lengerke Claudia⁷⁸²¹²²^ORCID,Majeti Ravindra⁶²³^ORCID,Weissman Irving L.⁶^ORCID,Rammensee Hans-Georg²³²²,Walz Juliane S.¹²³⁴^ORCID

Affiliation:

1. 1Department of Peptide-Based Immunotherapy, University and University Hospital Tübingen, Tübingen, Germany.

2. 2Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.

3. 3Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen, Germany.

4. 4Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.

5. 5Department of Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

6. 6Institute for Stem Cell Biology and Regenerative Medicine and the Ludwig Cancer Center, Stanford University School of Medicine, Stanford, California.

7. 7Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany.

8. 8Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.

9. 9Faculty of Medicine, Medical Center, Institute of Medical Bioinformatics and Systems Medicine (IBSM), University of Freiburg, Germany.

10. 10Department of Medicine I, University Hospital of Dresden, Dresden, Germany.

11. 11Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany.

12. 12Department of Otorhinolaryngology, Head and Neck Surgery, University of Tübingen, Tübingen, Germany.

13. 13Rudolf-Virchow-Zentrum, University Würzburg, Würzburg, Germany.

14. 14German Bone Marrow Donor Center (DKMS), Clinical Trials Unit, Dresden, Germany.

15. 15Institute of Immunology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

16. 16National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

17. 17German Cancer Consortium (DKTK), partner site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany.

18. 18Comprehensive Cancer Center Freiburg (CCCF), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

19. 19German Cancer Consortium (DKTK), Partner Site, Freiburg, and German Cancer Research Center (DKFZ), Heidelberg, Germany.

20. 20Centre for Integrative Biological Signalling Studies (CIBSS), University of Freiburg, Freiburg, Germany.

21. 21Clinic for Hematology, University of Basel and University Hospital Basel, Basel, Switzerland.

22. 22German Cancer Consortium (DKTK), DKFZ partner site Tübingen, Germany.

23. 23Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, California.

Abstract

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

Funder

Deutsche Forschungsgemeinschaft

Federal Ministry of Education and Research

German Cancer Consortium

Ernst Jung Prize for Medicine

Landesforschungspreis of Baden-Württemberg

Wilhelm Sander-Stiftung

Jose Carreras Leukämie Stiftung

Deutsche Krebshilfe

Swiss National Science Foundation

European Research Council

Else Kröner-Fresenius-Stiftung