Identification of the Targets of T-cell Receptor Therapeutic Agents and Cells by Use of a High-Throughput Genetic Platform
Identification of the Targets of T-cell Receptor Therapeutic Agents and Cells by Use of a High-Throughput Genetic Platform
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DOI：
10.1158/2326-6066.cir-19-0745
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发表时间：
2020-05-01
影响因子：
10.1
通讯作者：
Scheinberg, David A.
中科院分区：
文献类型：
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作者：
Gejman, Ron S.;Jones, Heather F.;Scheinberg, David A.
基于 T 细胞受体 (TCR) 的治疗细胞和药物已成为一类新的有效癌症疗法。这些疗法通过靶向 MHC 受体上展示的肽来作用于表达细胞内癌症相关蛋白的细胞。然而，这些药物与脱靶细胞和组织的交叉反应导致了严重的、有时是致命的不良事件。我们开发了一个高通量遗传平台（称为“PresentER”），该平台编码用于功能性免疫测定的 MHC-I 肽小基因，并确定 TCR 样治疗剂对大型 MHC-I 配体文库的反应性。在本文中，我们证明了 PresentER 可用于通过体外共培养测定或结合测定来识别 T 细胞和 TCR 模拟 (TCRm) 抗体的开关靶标。我们发现了数十种 MHC-I 配体，它们与两种 TCRm 抗体和两种天然 TCR 发生交叉反应，并且不易通过其他方法预测。
T-cell receptor (TCR)-based therapeutic cells and agents have emerged as a new class of effective cancer therapies. These therapies work on cells that express intracellular cancer-associated proteins by targeting peptides displayed on MHC receptors. However, cross-reactivities of these agents to off-target cells and tissues have resulted in serious, sometimes fatal, adverse events. We have developed a high-throughput genetic platform (termed "PresentER") that encodes MHC-I peptide minigenes for functional immunologic assays and determines the reactivities of TCR-like therapeutic agents against large libraries of MHC-I ligands. In this article, we demonstrated that PresentER could be used to identify the on-and-off targets of T cells and TCR-mimic (TCRm) antibodies using in vitro coculture assays or binding assays. We found dozens of MHC-I ligands that were cross-reactive with two TCRm antibodies and two native TCRs and that were not easily predictable by other methods.