Classification of chemotherapeutic agents based on their differential in vitro effects on dendritic cells.
Classification of chemotherapeutic agents based on their differential in vitro effects on dendritic cells.
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DOI：
10.1158/0008-5472.can-09-1101
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发表时间：
2009-09-01
期刊：
影响因子：
11.2
通讯作者：
Takashima A
中科院分区：
文献类型：
--
作者：
Tanaka H;Matsushima H;Mizumoto N;Takashima A
尽管树突状细胞（DC）在宿主抗肿瘤免疫中起着至关重要的作用，但许多化疗药物的药理学作用仍然是未知的。我们最近通过工程改造稳定的小鼠DC系XS 106，在IL-1β启动子的控制下表达黄色荧光蛋白（YFP）基因，开发了DC生物传感器克隆。在本研究中，所得XS 106 pIL 1-YFP DC克隆用于筛选54种抗癌药物。在5种浓度（0.1-10 μM）下测试每种药物对YFP表达、细胞活力和GM-CSF依赖性生长的影响。我们的无偏系统筛选揭示了显着的异质性之间的测试抗癌药物在其对三个功能参数的影响。有趣的是，15种药物在亚细胞毒性浓度下诱导显著的YFP表达，因此被归类为“DC刺激性”抗癌药物。随后发现这些药物诱导小鼠骨髓来源的DC中的至少一种特征性成熟变化。例如，长春碱（这类原型药物）诱导IL-1β、IL-6和IL-12的产生，CD 40、CD 80、CD 86和II类MHC的表面表达升高，以及DC的T细胞刺激能力增强。这些结果不仅说明了常用化疗药物对DC的不同药理作用，还为临床应用中基于合理性的抗癌药物选择和组合提供了概念框架。
Despite the crucial roles dendritic cells (DCs) play in host immunity against cancer, pharmacological effects of many chemotherapeutic agents have remained mostly unknown. We recently developed the DC biosensor clone by engineering the stable murine DC line XS106 to express the yellow fluorescent protein (YFP) gene under the control of IL-1β promoter. In this study, the resulting XS106 pIL1-YFP DC clone was used to screen 54 anticancer drugs. Each drug was tested at 5 concentrations (0.1-10 μM) for the effects on YFP expression, cell viability, and GM-CSF-dependent growth. Our unbiased systematic screening unveiled striking heterogeneity among the tested anticancer drugs in their effects on the three functional parameters. Interestingly, 15 drugs induced significant YFP expression at sub-cytotoxic concentrations and were, thus, categorized as “DC-stimulatory” anticancer drugs. These drugs were subsequently found to induce at least one of the characteristic maturational changes in mouse bone marrow-derived DCs. For example, vinblastine a prototypic drug of this class induced production of IL-1β, IL-6, and IL-12, elevated surface expression of CD40, CD80, CD86, and MHC class II, and an augmented T cell-stimulatory capacity of DCs. Not only do these results illustrate differential pharmacological effects of commonly used chemotherapeutic agents on DCs, they may also provide a conceptual framework for rationale-based selection and combination of anticancer drugs for clinical application.