Atypical acute myeloid leukemia-specific transcripts generate shared and immunogenic MHC class-I-associated epitopes
Atypical acute myeloid leukemia-specific transcripts generate shared and immunogenic MHC class-I-associated epitopes
复制标题
DOI：
10.1016/j.immuni.2021.03.001
复制
发表时间：
2021-04-13
期刊：
影响因子：
32.4
通讯作者：
Perreault, Claude
中科院分区：
文献类型：
--
作者：
Ehx, Gregory;Larouche, Jean-David;Perreault, Claude
急性髓性白血病（AML）没有受益于创新的免疫疗法，主要是因为缺乏可操作的免疫靶点。使用原始的蛋白质基因组学方法，我们分析了19例原发性AML样本的主要组织相容性复合体I类（MHC I类）相关免疫肽穹，并鉴定了58种肿瘤特异性抗原（TSAs）。这些tsa没有突变，并且主要（86%）来源于假定的非编码基因组区域。两种aml特异性畸变在tsa的生物发生、内含子保留和表观遗传变化中起着重要作用。事实上，48%的tsa是由内含子保留和翻译引起的，它们的RNA表达与表观遗传修饰因子（如DNMT3A）的突变有关。AML tsa编码转录本在患者中高度共享，并在母细胞和白血病干细胞中表达。在AML患者中，tsa的预测数量与同源T细胞受体克隆型的自发扩增、活化细胞毒性T细胞的积累、免疫编辑和生存率的提高相关。这些tsa代表了AML免疫治疗的有吸引力的靶点。
Acute myeloid leukemia (AML) has not benefited from innovative immunotherapies, mainly because of the lack of actionable immune targets. Using an original proteogenomic approach, we analyzed the major histocompatibility complex class I (MHC class I)-associated immunopeptidome of 19 primary AML samples and identified 58 tumor-specific antigens (TSAs). These TSAs bore no mutations and derived mainly (86%) from supposedly non-coding genomic regions. Two AML-specific aberrations were instrumental in the biogenesis of TSAs, intron retention, and epigenetic changes. Indeed, 48% of TSAs resulted from intron retention and translation, and their RNA expression correlated with mutations of epigenetic modifiers (e.g., DNMT3A). AML TSA-coding transcripts were highly shared among patients and were expressed in both blasts and leukemic stem cells. In AML patients, the predicted number of TSAs correlated with spontaneous expansion of cognate T cell receptor clonotypes, accumulation of activated cytotoxic T cells, immunoediting, and improved survival. These TSAs represent attractive targets for AML immunotherapy.