肿瘤细胞治疗研究
英文原题：Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells.
Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells.
此外，在成人肺至脑转移和儿童复发髓母细胞瘤的 CDX 模型中，ROBO1 CAR T 细胞在 50-100% 的小鼠中根除了肿瘤。
胶质母细胞瘤（GBM）是一种侵袭性脑肿瘤，对基因毒性疗法的耐药和肿瘤复发是其标志。在本研究中，我们通过整合基因组分析、患者来源GBM模型中的全基因组遗传扰动筛选以及独立的验证体系，研究了治疗后复发性GBM的功能驱动因素。在复发性肿瘤模型中发现了一致的特定遗传依赖，并伴有突变负荷增加，以及与其原发性GBM前身相比的转录本和蛋白表达差异。我们的观察提示，存在多层遗传反应驱动肿瘤复发，并表明PTP4A2（蛋白酪氨酸磷酸酶4A2）是复发性GBM中自我更新、增殖和致瘤性的调节因子。PTP4A2的遗传扰动或小分子抑制通过与roundabout引导受体1（ROBO1）及其下游分子作用因子形成的去磷酸化轴发挥作用，利用对ROBO信号传导的功能性依赖。由于pan-PTP4A抑制剂在体内因跨血脑屏障渗透性差而受限，我们设计了一种针对ROBO1的第二代嵌合抗原受体（CAR）T细胞疗法，ROBO1是一种在复发性GBM标本中富集的细胞表面受体。单剂ROBO1靶向CAR T细胞使复发性GBM的细胞系来源异种移植（CDX）模型的中位生存期翻倍。此外，在成人肺至脑转移和儿童复发髓母细胞瘤的CDX模型中，ROBO1 CAR T细胞在50-100%的小鼠中清除了肿瘤。我们的研究识别出一个有前景的可多重靶向PTP4A-ROBO1信号轴，其驱动复发性GBM的致瘤性，并在其他恶性脑肿瘤中具有潜力。
Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. In this study, we investigated functional drivers of post-treatment recurrent GBM through integrative genomic analyses, genome-wide genetic perturbation screens in patient-derived GBM models and independent lines of validation. Specific genetic dependencies were found consistent across recurrent tumor models, accompanied by increased mutational burden and differential transcript and protein expression compared to its primary GBM predecessor. Our observations suggest a multi-layered genetic response to drive tumor recurrence and implicate PTP4A2 (protein tyrosine phosphatase 4A2) as a modulator of self-renewal, proliferation and tumorigenicity in recurrent GBM. Genetic perturbation or small-molecule inhibition of PTP4A2 acts through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1) and its downstream molecular players, exploiting a functional dependency on ROBO signaling. Because a pan-PTP4A inhibitor was limited by poor penetrance across the blood-brain barrier in vivo, we engineered a second-generation chimeric antigen receptor (CAR) T cell therapy against ROBO1, a cell surface receptor enriched across recurrent GBM specimens. A single dose of ROBO1-targeted CAR T cells doubled median survival in cell-line-derived xenograft (CDX) models of recurrent GBM. Moreover, in CDX models of adult lung-to-brain metastases and pediatric relapsed medulloblastoma, ROBO1 CAR T cells eradicated tumors in 50-100% of mice. Our study identifies a promising multi-targetable PTP4A-ROBO1 signaling axis that drives tumorigenicity in recurrent GBM, with potential in other malignant brain tumors.
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