Loss of p53 impairs death receptor expression and confers resistance to CD19 CAR T-cell therapy in BCP-ALL

Blood Neoplasia Pub Date : 2025-02-01 DOI:10.1016/j.bneo.2024.100060

Willem P. J. Cox ∗ , Noël M. M. Dautzenberg ∗ , Linde Dekker , Tesa Klenovsek , Annelisa M. Cornel , Marliek van Hoesel , Dorette S. van Ingen Schenau , Reno S. Bladergroen , Roland P. Kuiper , Laurens T. van der Meer , Friso G. Calkoen † , Stefan Nierkens † , Frank N. van Leeuwen †

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Abstract

Loss of p53 function predicts a dismal outcome in relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Chimeric antigen receptor T-cell (CAR T) therapy was recently approved to salvage relapsed/refractory BCP-ALL. We observed a significantly worse overall survival after CD19-targeting CAR T therapy in children with TP53-mutated (TP53^Mut) compared with TP53–wild-type (TP53^WT) BCP-ALL. To investigate the effect of p53 loss on CAR T therapy response, we modeled TP53 mutations in 2 BCP-ALL cell lines and observed resistance to CAR T upon p53 loss. Moreover, expression analysis in cell lines and xenografts demonstrated that loss of p53 abrogates the expression of the death receptors Fas and death receptor 5 (DR5), both implicated in CAR T cytotoxicity. Conversely, ectopic expression of Fas improved CAR T cytotoxicity. Furthermore, p53 stabilization induced expression of both Fas and DR5, accompanied by increased CAR T–mediated killing. Although these findings provide mechanistic insight into why CAR T therapy fails against TP53^Mut BCP-ALL, they may also provide opportunities to enhance the efficacy of CAR T treatment both in patients with TP53^Mut and TP53^WT BCP-ALL. Furthermore, these data underscore the need for alternative curative therapies for this very high-risk patient group.

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在BCP-ALL中，p53的缺失会损害死亡受体的表达，并导致CD19 CAR - t细胞治疗产生耐药性

摘要p53功能缺失预示着复发性b细胞前体急性淋巴细胞白血病（BCP-ALL）的预后不佳。嵌合抗原受体T细胞（CAR - T）疗法最近被批准用于挽救复发/难治性BCP-ALL。我们观察到，与p53野生型（TP53WT） BCP-ALL相比，p53突变（TP53Mut）儿童在接受cd19靶向CAR - T治疗后的总生存率显著降低。为了研究p53缺失对CAR - T治疗反应的影响，我们在2个BCP-ALL细胞系中模拟了TP53突变，并观察了p53缺失对CAR - T的抵抗。此外，细胞系和异种移植物的表达分析表明，p53的缺失会消除死亡受体Fas和死亡受体5 （DR5）的表达，这两种受体都与CAR - T细胞毒性有关。相反，异位表达Fas可改善CAR - T细胞毒性。此外，p53稳定诱导Fas和DR5的表达，并伴有CAR - t介导的杀伤增加。尽管这些发现提供了CAR - T疗法治疗TP53Mut - BCP-ALL失败的机制，但它们也可能为提高CAR - T治疗TP53Mut和TP53WT - BCP-ALL患者的疗效提供了机会。此外，这些数据强调了对这一高危患者群体进行替代治疗的必要性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Blood Neoplasia

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