Cox Willem P J, Dautzenberg Noël M M, Dekker Linde, Klenovsek Tesa, Cornel Annelisa M, van Hoesel Marliek, van Ingen Schenau Dorette S, Bladergroen Reno S, Kuiper Roland P, van der Meer Laurens T, Calkoen Friso G, Nierkens Stefan, van Leeuwen Frank N
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
Blood Neoplasia. 2024 Nov 29;2(1):100060. doi: 10.1016/j.bneo.2024.100060. eCollection 2025 Feb.
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 -mutated ( ) compared with -wild-type ( ) BCP-ALL. To investigate the effect of p53 loss on CAR T therapy response, we modeled 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 BCP-ALL, they may also provide opportunities to enhance the efficacy of CAR T treatment both in patients with and BCP-ALL. Furthermore, these data underscore the need for alternative curative therapies for this very high-risk patient group.
p53功能丧失预示着复发的B细胞前体急性淋巴细胞白血病（BCP-ALL）患者预后不佳。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（WT）BCP-ALL儿童相比，p53突变（p53mut）的儿童在接受靶向CD19的CAR T治疗后的总生存期明显更差。为了研究p53缺失对CAR T治疗反应的影响，我们在2种BCP-ALL细胞系中模拟了p53突变，发现p53缺失会导致对CAR T产生抗性。此外，对细胞系和异种移植瘤的表达分析表明，p53缺失会消除死亡受体Fas和死亡受体5（DR5）的表达，而这两种受体都与CAR T细胞毒性有关。相反，Fas的异位表达可提高CAR T细胞毒性。此外，p53的稳定化诱导了Fas和DR5的表达，同时增强了CAR T介导的杀伤作用。尽管这些发现为CAR T治疗对p53mut BCP-ALL无效的原因提供了机制上的见解，但它们也可能为提高CAR T治疗对p53mut和p53WT BCP-ALL患者的疗效提供机会。此外，这些数据强调了为这一极高风险患者群体寻求替代治愈性疗法的必要性。
