Blood:死亡受体信号调节CAR-T细胞毒性

2019-12-13 QQY MedSci原创

嵌合抗原受体(CAR)T细胞疗法已被证实对于复发性/难治性B细胞恶性肿瘤具有一定疗效,但仍有一定的耐药或复发病例出现。深入了解影响CAR T细胞毒性的机制和通过小分子药物调控的潜在机制有助于改善目前的免疫疗法。

中心点:

通过对500多种药物的免疫调节作用进行调查发现,SMAC是CAR -T细胞毒性的增敏剂。

基因组水平的CRISPR筛选揭示了细胞死亡受体信号对于CAR-T细胞毒性的重要性。

摘要:

嵌合抗原受体(CAR)T细胞疗法已被证实对于复发性/难治性B细胞恶性肿瘤具有一定疗效,但仍有一定的耐药或复发病例出现。深入了解影响CAR T细胞毒性的机制和通过小分子药物调控的潜在机制有助于改善目前的免疫疗法。

现研究人员使用了500多种小分子药物和基因组级的CRISPR-Cas9功能缺失筛选,系统地研究了CAR T细胞毒性的药物机制。结果显示多种酪氨酸激酶抑制剂可通过破坏T细胞信号的转录活性抑制CAR T细胞毒性。相反,促凋亡小分子药物SMAC类似物可增加急性B淋巴细胞白血病(B-ALL)和弥漫性大B细胞淋巴瘤(DLBCL)细胞对抗CD19 CAR T细胞的敏感性。

CRISPR筛选通过FADD和TNFRSF10B (TRAIL-R2)作为CAR T细胞毒性的关键介质筛选出死亡受体信号,并阐明了SMAC类似物致敏的RIPK1依赖机制。死亡受体的表达在B细胞恶性肿瘤的基因亚型中存在差异,提示CAR T细胞的细胞毒性机制与癌症遗传有关。

综上所述,本研究结果提示死亡受体信号是癌细胞对CAR-T细胞毒性敏感性的重要调节因子,具有通过药物靶向增强癌症免疫治疗效果的潜力。本研究揭示了癌症药物的免疫调节特性和影响CAR T细胞毒性的遗传机制。

原始出处:

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    2020-05-23 仁者大医
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