CD8 co-receptor modulates the specificity profile of the 1G4 TCR against NY-ESO-1.

IF 12 1区医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Molecular Therapy Pub Date : 2025-10-06 DOI:10.1016/j.ymthe.2025.10.006

Heather F Jones,Zita Aretz,Ron S Gejman,Tara Cicic,David A Scheinberg

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引用次数: 0

Abstract

Engineered T cells have shown efficacy in cancer treatment. However, the promiscuity of TCR engineered T cells may result in recognition of off-target epitopes, causing severe toxicities. A genetic screen of >3,000 proteomic epitopes in the MHC-I ligandome uncovered off-target peptides for both, native and affinity enhanced 1G4 TCR, which target cancer antigen NY-ESO-1/A02 expressing cells. We validated off-target peptides derived from the human proteome recognized by both TCRs, showing that the affinity enhanced TCR has more off-targets. Multiple off-target epitopes were reactive only in CD8 T cells, not in CD4 T cells. We identified a previously undescribed class of CD8 receptor dependent off-targets. CD8α negative cells (CD8α-/-) 1G4 T cells had fewer off-target reactivities, enhancing on-target specificity in vitro and in vivo. We corroborated our findings with the DMF5 TCR, targeting MART1/A02. This research advances our understanding of the distinct roles that CD4 and CD8 proteins play in T cell antigen recognition, potentially leading to more specific, effective, and safer engineered T cell therapies.

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CD8共受体调节1G4 TCR对NY-ESO-1的特异性。

工程T细胞已经在癌症治疗中显示出疗效。然而，TCR工程T细胞的混杂性可能导致脱靶表位的识别，从而引起严重的毒性。通过对MHC-I配体中约3000个蛋白质组表位的遗传筛选，发现了针对肿瘤抗原NY-ESO-1/A02表达细胞的天然和亲和增强1G4 TCR的脱靶肽。我们验证了来自两种TCR识别的人类蛋白质组的脱靶肽，表明亲和性增强的TCR具有更多的脱靶。多个脱靶表位仅在CD8 T细胞中有反应，而在CD4 T细胞中无反应。我们确定了先前描述的一类依赖CD8受体的脱靶。CD8α阴性细胞（CD8α-/-） 1G4 T细胞脱靶反应性较弱，体外和体内靶特异性增强。我们用靶向MART1/A02的DMF5 TCR证实了我们的发现。这项研究促进了我们对CD4和CD8蛋白在T细胞抗原识别中的独特作用的理解，可能导致更特异性、更有效和更安全的工程化T细胞疗法。

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

Molecular Therapy 医学-生物工程与应用微生物

CiteScore

19.20

自引率

3.20%

发文量

357

审稿时长

3 months

期刊介绍： Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.