SCAN-ACT: adoptive T cell therapy target discovery through single-cell transcriptomics.

IF 10.4 1区 生物学 Q1 GENETICS & HEREDITY
Stefano Testa, Aastha Pal, Ajay Subramanian, Sushama Varma, Jack Pengfei Tang, Danielle Graham, Sara Arfan, Minggui Pan, Nam Q Bui, Kristen N Ganjoo, Sarah Dry, Paul Huang, Matt van de Rijn, Wei Jiang, Anusha Kalbasi, Everett J Moding
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引用次数: 0

Abstract

Background: The FDA approval of T cell receptor-engineered T cells (TCR-T) for synovial sarcoma demonstrates the potential for adoptive T cell therapies (ACTs) in solid tumors. However, the paucity of tumor-associated targets without expression in normal tissues remains a major bottleneck, especially in rare cancer subtypes.

Methods: We developed a comprehensive computational pipeline called SCAN-ACT that leverages single-cell RNA sequencing and multi-omics data from tumor and normal tissues to nominate and prioritize putative targets for both chimeric antigen receptor (CAR)- and TCR-T cells. For surface membrane targets, SCAN-ACT proposes monospecific targets and potential target pairs for bispecific Boolean logic-gated CAR T cells. For peptide-MHC targets, SCAN-ACT proposes intracellular peptides bound to a diverse set of human leukocyte antigens. Selected targets were validated experimentally by protein expression and for peptide-MHC binding.

Results: We applied the SCAN-ACT pipeline to soft tissue sarcoma (STS), analyzing 986,749 single cells to identify and prioritize 395 monospecific CAR-T targets, 14,192 bispecific CAR-T targets, and 5020 peptide-MHC targets for TCR-T cells. Proposed targets and target pairs reflected the mesenchymal, neuronal, and hematopoietic ontogeny of STS. We further validated SCAN-ACT in glioblastoma revealing its versatility.

Conclusions: This work provides a robust data repository along with a web-based and user-friendly set of analysis tools to accelerate ACT development for solid tumors ( https://scanact.stanford.edu/ ).

SCAN-ACT:通过单细胞转录组学发现过继性T细胞治疗靶点。
背景:FDA批准T细胞受体工程T细胞(TCR-T)治疗滑膜肉瘤,表明过继T细胞治疗(ACTs)在实体瘤中的潜力。然而,缺乏在正常组织中不表达的肿瘤相关靶点仍然是一个主要的瓶颈,特别是在罕见的癌症亚型中。方法:我们开发了一个名为SCAN-ACT的综合计算管道,利用来自肿瘤和正常组织的单细胞RNA测序和多组学数据来指定和优先考虑嵌合抗原受体(CAR)-和TCR-T细胞的假设靶点。对于表面膜靶点,SCAN-ACT提出了双特异性布尔逻辑门控CAR - T细胞的单特异性靶点和潜在靶点对。对于多肽- mhc靶点,SCAN-ACT提出了与多种人类白细胞抗原结合的细胞内肽。选择的靶点通过蛋白表达和肽- mhc结合进行实验验证。结果:我们将SCAN-ACT管道应用于软组织肉瘤(STS),分析了986,749个单细胞,鉴定并优先考虑了395个单特异性CAR-T靶点,14,192个双特异性CAR-T靶点和5020个TCR-T细胞的肽- mhc靶点。提出的靶点和靶点对反映了STS的间质、神经元和造血个体发生。我们进一步验证了SCAN-ACT在胶质母细胞瘤中的应用,揭示了其多功能性。结论:这项工作提供了一个强大的数据存储库,以及一套基于网络和用户友好的分析工具,以加速实体瘤ACT的开发(https://scanact.stanford.edu/)。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Genome Medicine
Genome Medicine GENETICS & HEREDITY-
CiteScore
20.80
自引率
0.80%
发文量
128
审稿时长
6-12 weeks
期刊介绍: Genome Medicine is an open access journal that publishes outstanding research applying genetics, genomics, and multi-omics to understand, diagnose, and treat disease. Bridging basic science and clinical research, it covers areas such as cancer genomics, immuno-oncology, immunogenomics, infectious disease, microbiome, neurogenomics, systems medicine, clinical genomics, gene therapies, precision medicine, and clinical trials. The journal publishes original research, methods, software, and reviews to serve authors and promote broad interest and importance in the field.
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