Simultaneously target of normal and stem cells-like gastric cancer cells via cisplatin and anti-CD133 CAR-T combination therapy
Simultaneously target of normal and stem cells-like gastric cancer cells via cisplatin and anti-CD133 CAR-T combination therapy
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DOI：
10.1007/s00262-021-02891-x
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发表时间：
2021-02-26
影响因子：
5.8
通讯作者：
Xuan, Yi
中科院分区：
文献类型：
--
作者：
Han, Yang;Sun, Bo;Xuan, Yi
CD133+癌症干细胞在多种侵袭性癌症中介导化疗耐药性，在本研究中，抗CD133嵌合抗原受体T（CAR-T）细胞被设计用于选择性靶向顺铂耐药的胃癌干细胞。检测胃癌患者顺铂治疗前后CD133的相对表达量。将抗CD133 CAR-T细胞与顺铂暴露的CD133(+) BGC-823细胞一起孵育以评估杀伤效果。同时，通过荧光激活细胞分选法检测经典T细胞激活标记物，并通过酶联免疫吸附测定法检测功能性细胞因子谱。除了CD133阳性干细胞样细胞的百分比外，还测量了BGC-823、KATO III和MKN-28异种移植模型中皮下肿瘤的体积和重量，以评估顺铂和抗CD133 CAR-T联合策略的抗肿瘤活性。顺铂处理后，人类样本和 BGC-823 细胞均显示 CD133 表达上调。抗CD133 CAR-T细胞对顺铂暴露的CD133(+) BGC-823细胞表现出显着的杀伤效率，并上调激活标记和细胞毒性细胞因子的产生。此外，顺铂和抗 CD133 CAR-T 联合治疗可抑制三种不同异种移植模型中的肿瘤进展，并减少 CD133 阳性干细胞样细胞浸润。这些结果表明顺铂和抗CD133 CAR-T联合策略可以同时靶向正常和干细胞样胃癌细胞以改善治疗结果。
CD133 + cancer stem cells mediate chemoresistance in multiple aggressive cancers, and anti-CD133 chimeric antigen receptor T (CAR-T) cells are designed to selectively target cisplatin-resistant gastric cancer stem cells in this investigation. The relative CD133 expression was detected in gastric cancer patients before and after cisplatin treatment. Anti-CD133 CAR-T cells were incubated with cisplatin-exposed CD133(+) BGC-823 cells to evaluate the killing efficacy. At the same time, the canonical T cell activation markers were assayed by fluorescence-activated cell sorting, and the functional cytokine profile was detected with enzyme-linked immunosorbent assays. In addition to the percentage of CD133 positive stem cell-like cells, the volume and weight of subcutaneous tumors in BGC-823, KATO III and MKN-28 xenograft models were measured to evaluate the anti-tumor activity of cisplatin and anti-CD133 CAR-T combination strategy. After cisplatin treatment, both human samples and BGC-823 cells showed up-regulated CD133 expression. Anti-CD133 CAR-T cells exhibited pronounced killing efficiency against cisplatin-exposed CD133(+) BGC-823 cells with up-regulated activation markers and cytotoxicity cytokine production. Moreover, cisplatin and anti-CD133 CAR-T combination treatment inhibited tumor progression in three different xenograft models with diminished CD133 positive stem cell-like cell infiltration. These results indicate that cisplatin and anti-CD133 CAR-T combination strategy can simultaneously target normal and stem cell-like gastric cancer cells to improve the treatment outcome.