Impaired Death Receptor Signaling in Leukemia Causes Antigen-Independent Resistance by Inducing CAR T-cell Dysfunction
Impaired Death Receptor Signaling in Leukemia Causes Antigen-Independent Resistance by Inducing CAR T-cell Dysfunction
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DOI：
10.1158/2159-8290.cd-19-0813
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发表时间：
2020-04-01
期刊：
影响因子：
28.2
通讯作者：
Ruella, Marco
中科院分区：
文献类型：
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作者：
Singh, Nathan;Lee, Yong Gu;Ruella, Marco
10%-20%的急性淋巴细胞白血病（ALL）患者对CD 19导向的嵌合抗原受体T细胞疗法（CART 19）存在原发性耐药;然而，这种耐药的机制仍然难以捉摸。使用全基因组功能丧失筛选，我们发现尽管CART 19治疗，ALL中受损的死亡受体信号传导仍导致疾病快速进展。这是由对T细胞细胞毒性的固有抗性介导的，其允许抗原持久性，并且随后通过诱导CAR T细胞功能损伤而放大。这些发现使用来自ALL的两项CAR T细胞临床试验的样本进行了验证，我们发现死亡受体基因表达减少与总体生存率降低和T细胞适应性降低相关。我们的研究结果表明，ALL中死亡受体信号传导的固有失调通过损害T细胞的细胞毒性和促进进行性CAR T细胞功能障碍直接导致CAR T细胞衰竭。意义：对CART 19的耐药性是B细胞恶性肿瘤治疗疗效的重要障碍。这项工作表明，肿瘤细胞中受损的死亡受体信号传导导致CART 19细胞毒性失败，并驱动CART 19功能障碍，确定了对CAR治疗的抗原非依赖性抗性的新机制。
Primary resistance to CD19-directed chimeric antigen receptor T-cell therapy (CART19) occurs in 10% to 20% of patients with acute lymphoblastic leukemia (ALL); however, the mechanisms of this resistance remain elusive. Using a genome-wide loss-of-function screen, we identified that impaired death receptor signaling in ALL led to rapidly progressive disease despite CART19 treatment. This was mediated by an inherent resistance to T-cell cytotoxicity that permitted antigen persistence and was subsequently magnified by the induction of CAR T-cell functional impairment. These findings were validated using samples from two CAR T-cell clinical trials in ALL, where we found that reduced expression of death receptor genes was associated with worse overall survival and reduced T-cell fitness. Our findings suggest that inherent dysregulation of death receptor signaling in ALL directly leads to CAR T-cell failure by impairing T-cell cytotoxicity and promoting progressive CAR T-cell dysfunction.SIGNIFICANCE: Resistance to CART19 is a significant barrier to efficacy in the treatment of B-cell malignancies. This work demonstrates that impaired death receptor signaling in tumor cells causes failed CART19 cytotoxicity and drives CART19 dysfunction, identifying a novel mechanism of antigen-independent resistance to CAR therapy.