Expression profiling of TCR-engineered T cells demonstrates overexpression of multiple inhibitory receptors in persisting lymphocytes
Expression profiling of TCR-engineered T cells demonstrates overexpression of multiple inhibitory receptors in persisting lymphocytes
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DOI：
10.1182/blood-2013-04-495531
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发表时间：
2013-08-22
期刊：
影响因子：
20.3
通讯作者：
Morgan, Richard A.
中科院分区：
文献类型：
--
作者：
Abate-Daga, Daniel;Hanada, Ken-ichi;Morgan, Richard A.
尽管使用基因工程T细胞的过继性细胞转移疗法（ACT）的开发取得了重大进展，但人们对输注后细胞的命运知之甚少。为了解决这一问题，我们对给药后1个月持续存在于循环中的T细胞受体工程化淋巴细胞和输注的产品之间的基因表达进行了比较分析。我们观察到156个与免疫功能相关的基因差异表达，包括淋巴细胞功能刺激因子的低表达和抑制基因在输注后细胞中的过表达。在输注后过度表达的基因中，程序性细胞死亡1（PDCD 1）产物（共抑制受体PD-1）在输注后淋巴细胞中的表达百分比高于输注产物。这与通过与其配体PD-L1相互作用抑制细胞因子产生的更高敏感性相关。共抑制受体CD 160也在持续细胞中过表达，并且其表达与反应性降低相关，这令人惊讶地被发现是配体独立的。这些结果有助于更深入地了解用于治疗人类恶性肿瘤的转基因淋巴细胞的特性，并可能为开发联合治疗作为改善ACT的方法提供依据。本试验在www.clinicaltrials.gov上注册为#NCT 00509288、#NCT 00923195和#NCT 01273181。
Despite significant progress in the development of adoptive cell-transfer therapies (ACTs) using gene-engineered T cells, little is known about the fate of cells following infusion. To address that, we performed a comparative analysis of gene expression between T-cell receptor-engineered lymphocytes persisting in the circulation 1 month after administration and the product that was infused. We observed that 156 genes related to immune function were differentially expressed, including underexpression of stimulators of lymphocyte function and overexpression of inhibitory genes in postinfusion cells. Of genes overexpressed postinfusion, the product of programmed cell death 1 (PDCD1), coinhibitory receptor PD-1, was expressed at a higher percentage in postinfusion lymphocytes than in the infusion product. This was associated with a higher sensitivity to inhibition of cytokine production by interaction with its ligand PD-L1. Coinhibitory receptor CD160 was also overexpressed in persisting cells, and its expression was associated with decreased reactivity, which surprisingly was found to be ligand-independent. These results contribute to a deeper understanding of the properties of transgenic lymphocytes used to treat human malignancies and may provide a rationale for the development of combination therapies as a method to improve ACT. This trial was registered at www.clinicaltrials.gov as #NCT00509288, #NCT00923195, and #NCT01273181.