预测血液癌中针对Wilms肿瘤1抗原特异性t细胞免疫

IF 13.4 1区 医学 Q1 HEMATOLOGY
Brittany L. Ford, Emmi Jokinen, Jani Huuhtanen, Sofia Forstén, Jay Klievink, Gabriella Antignani, Oscar Brück, Vincenzo Cerullo, Karita Peltonen, Satu Mustjoki
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引用次数: 0

摘要

Wilms tumor 1 (WT1)是一种在实体瘤和血液系统恶性肿瘤中表达的肿瘤相关抗原。针对WT1的t细胞免疫疗法目前正在开发中。为了分析内源性t细胞对WT1的反应,我们训练了能够从t细胞受体(TCR)测序数据中检测WT1特异性t细胞反应的计算模型。我们用VLDFAPPGA (VLD, WT137-45)和RMFPNAPYL (RMF, WT1126-134)肽段对健康供体和急性髓性白血病(AML)患者样本进行肽脉冲,然后用单细胞RNA + TCRαβ测序对WT1右旋聚物阳性CD8 + t细胞进行测序。TCRGP机器学习TCR分类方法使用表位特异性和对照TCR库进行训练,我们获得了AUROC值为0.74 (VLD)和0.75 (RMF),可以可靠地识别wt1特异性t细胞。在大量TCRβ测序的患者样本(AML n = 21,慢性髓性白血病(CML) n = 26,骨髓增生异常综合征n = 25)中,wt1特异性t细胞丰度中位数与健康对照相似,但他们的VLD和rmf特异性TCR库表现出更高的克隆性,其中两名患者呈现高达13%的wt1特异性t细胞。AML骨髓t细胞的ScRNA+TCRαβ测序显示wt1特异性t细胞主要表现为效应或末端效应记忆表型。总之,我们的新计算模型可以从TCR测序数据集和白血病抗原特异性免疫反应监测中大规模识别wt1特异性t细胞。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Predicting antigen-specific T-cell immunity against Wilms tumor 1 in hematologic cancer

Predicting antigen-specific T-cell immunity against Wilms tumor 1 in hematologic cancer

Wilms tumor 1 (WT1) is a tumor-associated antigen expressed in solid tumors and hematological malignancies. T-cell immunotherapies targeting WT1 are currently under development. To analyze endogenous T-cell responses against WT1, we trained computational models capable of detecting WT1-specific T-cell responses from T-cell receptor (TCR) sequencing data. We peptide-pulsed healthy donor and acute myeloid leukemia (AML) patient samples with VLDFAPPGA (VLD, WT137-45) and RMFPNAPYL (RMF, WT1126-134) peptides, then sequenced the WT1 dextramer-positive CD8 + T-cells with single-cell RNA + TCRαβ sequencing. The TCRGP machine-learning TCR-classification method was trained with epitope-specific and control TCR repertoires, and we obtained AUROC values of 0.74 (VLD) and 0.75 (RMF), allowing reliable identification of WT1-specific T-cells. In bulk TCRβ sequenced patient samples (AML n = 21, chronic myeloid leukemia (CML) n = 26, and myelodysplastic syndrome n = 25), the median WT1-specific T-cell abundance was similar to healthy controls, but their VLD and RMF-specific TCR repertoires exhibited higher clonality with two patients presenting up to 13% of WT1-specific T-cells. ScRNA+TCRαβ sequencing of AML bone marrow T-cells revealed that WT1-specific T-cells predominantly exhibit an effector or terminal effector memory phenotype. In conclusion, our novel computational models enable large-scale WT1-specific T-cell identification from TCR sequencing datasets and leukemia-antigen-specific immune response monitoring.

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来源期刊
Leukemia
Leukemia 医学-血液学
CiteScore
18.10
自引率
3.50%
发文量
270
审稿时长
3-6 weeks
期刊介绍: Title: Leukemia Journal Overview: Publishes high-quality, peer-reviewed research Covers all aspects of research and treatment of leukemia and allied diseases Includes studies of normal hemopoiesis due to comparative relevance Topics of Interest: Oncogenes Growth factors Stem cells Leukemia genomics Cell cycle Signal transduction Molecular targets for therapy And more Content Types: Original research articles Reviews Letters Correspondence Comments elaborating on significant advances and covering topical issues
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