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

IF 11.5 Q1 HEMATOLOGY
Annika Nelde, Heiko Schuster, Jonas S Heitmann, Jens Bauer, Yacine Maringer, Melissa Zwick, Jens-Peter Volkmer, James Y Chen, Anna M Paczulla Stanger, Ariane Lehmann, Bismark Appiah, Melanie Märklin, Elke Rücker-Braun, Helmut R Salih, Malte Roerden, Sarah M Schroeder, Max-Felix Häring, Andreas Schlosser, Johannes Schetelig, Marc Schmitz, Melanie Boerries, Natalie Köhler, Claudia Lengerke, Ravindra Majeti, Irving L Weissman, Hans-Georg Rammensee, Juliane S Walz
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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.

白血病祖细胞HLA抗原介导的急性粒细胞白血病免疫监测。
耐药白血病干细胞和祖细胞(LSC)是急性粒细胞白血病(AML)复发的主要原因。LSC靶向治疗可以改善AML患者的预后。在这里,我们证明LSCs呈现HLA限制性抗原,诱导T细胞反应,从而对AML进行免疫监测。使用基于质谱的免疫肽组学方法,我们表征了患者LSCs的抗原景观,并鉴定了正常组织中不存在的AML和AML/LSC相关HLA呈递的抗原,包括非突变肽、神秘新表位和NPM1和IDH2常见AML驱动突变的新表位。共享AML/LSC抗原的功能相关性通过其在患者中的识别记忆T细胞的存在来说明。抗原特异性T细胞识别和HLA II类免疫肽多样性与临床结果相关。总之,AML和LSCs之间共享的这些抗原代表了基于T细胞的治疗的主要靶点,有可能消除AML患者中残留的LSCs。意义:消除耐药白血病干细胞和祖细胞(LSC)仍然是AML治疗中的一个主要挑战。本研究鉴定并功能验证了LSC相关的HLA I类和HLA II类呈递抗原,为开发LSC指导的基于T细胞的AML患者免疫治疗方法铺平了道路。见里兹的相关评论,第437页。
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来源期刊
CiteScore
12.70
自引率
1.80%
发文量
139
期刊介绍: The journal Blood Cancer Discovery publishes high-quality Research Articles and Briefs that focus on major advances in basic, translational, and clinical research of leukemia, lymphoma, myeloma, and associated diseases. The topics covered include molecular and cellular features of pathogenesis, therapy response and relapse, transcriptional circuits, stem cells, differentiation, microenvironment, metabolism, immunity, mutagenesis, and clonal evolution. These subjects are investigated in both animal disease models and high-dimensional clinical data landscapes. The journal also welcomes submissions on new pharmacological, biological, and living cell therapies, as well as new diagnostic tools. They are interested in prognostic, diagnostic, and pharmacodynamic biomarkers, and computational and machine learning approaches to personalized medicine. The scope of submissions ranges from preclinical proof of concept to clinical trials and real-world evidence. Blood Cancer Discovery serves as a forum for diverse ideas that shape future research directions in hematooncology. In addition to Research Articles and Briefs, the journal also publishes Reviews, Perspectives, and Commentaries on topics of broad interest in the field.
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