Altered Peptide Ligands Impact the Diversity of Polyfunctional Phenotypes in T Cell Receptor Gene-Modified T Cells.
Altered Peptide Ligands Impact the Diversity of Polyfunctional Phenotypes in T Cell Receptor Gene-Modified T Cells.
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改变的肽配体影响 T 细胞受体基因修饰 T 细胞中多功能表型的多样性。
DOI：
10.1016/j.ymthe.2018.01.015
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Nishimura,MichaelI
中科院分区：
文献类型：
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作者：
Spear,TimothyT;Wang,Yuan;SmithJr,ThomasW;Simms,PatriciaE;Garrett-Mayer,Elizabeth;Hellman,LanceM;Baker,BrianM;Nishimura,MichaelI
在过继性细胞转移中使用T细胞受体（TCR）基因修饰的T细胞已经取得了有希望的临床成功，但通常，简单的临床前评估不一定能准确预测治疗效果或安全性。临床前研究通常评估一种或有限数量的1型细胞因子以评估抗原识别。然而，最近的研究表明，其他“分型”T细胞在有效的抗肿瘤/病毒免疫中，有限的功能评估可能会低估交叉反应性。在这项研究中，我们使用一个改变的肽配体（APL）模型和多维流式细胞术来评估TCR基因修饰的T细胞的多功能性。评估六种细胞因子和裂解标志物CD 107 a在每个细胞的基础上揭示了显着不同的多功能表型内的单个T细胞培养和外周血淋巴细胞（PBL）捐助者。该多功能评估确定了意想不到的表型，包括产生1型和2型细胞因子的细胞，并强调了我们先前研究中忽略的干扰素γ阴性（IFNγ阴性）抗原反应性群体。此外，APLs使功能表型倾向于不太多功能，这与TCR-肽-主要组织相容性复合物（pMHC）亲和力的变化不一定相关。更好地了解基因修饰的T细胞功能多样性可能有助于确定最佳的治疗表型，预测临床反应，预测脱靶识别，并改善TCR基因修饰的T细胞的设计和递送。
The use of T cell receptor (TCR) gene-modified T cells in adoptive cell transfer has had promising clinical success, but often, simple preclinical evaluation does not necessarily accurately predict treatment efficacy or safety. Preclinical studies generally evaluate one or a limited number of type 1 cytokines to assess antigen recognition. However, recent studies have implicated other "typed" T cells in effective anti-tumor/viral immunity, and limited functional evaluations may underestimate cross-reactivity. In this study, we use an altered peptide ligand (APL) model and multi-dimensional flow cytometry to evaluate polyfunctionality of TCR gene-modified T cells. Evaluating six cytokines and the lytic marker CD107a on a per cell basis revealed remarkably diverse polyfunctional phenotypes within a single T cell culture and among peripheral blood lymphocyte (PBL) donors. This polyfunctional assessment identified unexpected phenotypes, including cells producing both type 1 and type 2 cytokines, and highlighted interferon γneg(IFNγneg) antigen-reactive populations overlooked in our previous studies. Additionally, APLs skewed functional phenotypes to be less polyfunctional, which was not necessarily related to changes in TCR-peptide-major histocompatibility complex (pMHC) affinity. A better understanding of gene-modified T cell functional diversity may help identify optimal therapeutic phenotypes, predict clinical responses, anticipate off-target recognition, and improve the design and delivery of TCR gene-modified T cells.