Testing the Specificity of Compounds Designed to Inhibit CPT1A in T Cells.
Testing the Specificity of Compounds Designed to Inhibit CPT1A in T Cells.
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DOI：
10.1007/978-1-0716-0203-4_5
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Milone MC
中科院分区：
文献类型：
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作者：
O'Connor RS;Milone MC
作为对抗原和共刺激的反应，T细胞经历了一系列的代谢转变，以满足克隆扩增、分化和效应器功能的生物合成需求。在抗原清除后，长链脂肪酸的氧化参与了效应T细胞向中枢记忆T细胞的转变。然而，表明LCFAO在记忆T细胞发育中的作用的研究在很大程度上依赖于依托托莫昔尔(ETO)的使用，ETO是一种长链脂肪酸转运体CPT1A的小分子抑制剂。了解肿瘤微环境中可能发生的包括LCFA在内的营养物质的枯竭如何影响T细胞的增殖、分化和功能，对肿瘤免疫治疗具有重要意义。在这里，我们结合转录后基因沉默的分析和细胞外通量分析来确定依托莫昔尔是否在氧化代谢中发挥非特异性作用。我们描述的ETO的非靶点效应突出了在T细胞功能丧失途径中使用药物抑制剂的挑战。
In response to antigen and costimulation, T cells undergo a series of metabolic transitions that fulfill the biosynthetic demands of clonal expansion, differentiation, and effector function. Following antigen clearance, the oxidation of long-chain fatty acids (LCFAO) has been implicated in the transition from effector to central memory T cells. However, studies demonstrating a role for LCFAO in memory T-cell development have largely relied on the use of etomoxir (ETO), a small molecule inhibitor of the long-chain fatty acid transporter CPT1A. Understanding how the depletion of nutrients including LCFA that might occur in tumor microenvironments affects T-cell proliferation, differentiation, and function has important implications for tumor immunotherapy. Here, we combine the analysis of posttranscriptional gene silencing with extracellular flux assays to determine if etomoxir exerts nonspecific effects on oxidative metabolism. The off-target effects of ETO that we describe highlight the challenges of using pharmacologic inhibitors in loss-of-function approaches in T cells.