Mesenchymal stem cell carriers enhance antitumor efficacy induced by oncolytic reovirus in acute myeloid leukemia
Mesenchymal stem cell carriers enhance antitumor efficacy induced by oncolytic reovirus in acute myeloid leukemia
复制标题
间充质干细胞载体增强溶瘤呼肠孤病毒诱导的急性髓系白血病的抗肿瘤功效
DOI：
10.1016/j.intimp.2021.107437
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发表时间：
2021
影响因子：
5.6
通讯作者：
He Zhixu
中科院分区：
文献类型：
--
作者：
Wang Xianyao;Yang Yichen;Wang Nianxue;Wu Xijun;Xu Jianwei;Zhou Yanhua;Zhao Xing;He Zhixu
化疗是急性髓细胞白血病（AML）的主要治疗方法，但疗效不佳，最常见的表现为缓解后复发。因此，提高AML的长期生存率是一个关键的临床挑战。近年来，溶瘤病毒疗法为AML治疗提供了另一种方法。溶瘤呼肠孤病毒的使用已经在30多个临床试验中探索了安全性和可行性问题。然而，与其他溶瘤病毒一样，中和抗体（NAb）降低了治疗效果。为了解决这一问题，人脐带间充质干细胞（human umbilical cord mesenchymal stem cells，hUC-MSCs）被用于在体外和体内模型中递送呼肠孤病毒。人UC-MSCs成功负载呼肠孤病毒，且不影响其生物学功能，我们还研究了在NAbs存在下hUC-MSCs对呼肠孤病毒的体外保护作用。在免疫受损的AML小鼠模型中，hUC-MSC有效地将呼肠孤病毒携带至肿瘤病变，并且在高滴度抗呼肠孤病毒抗体存在下显著延长了小鼠中AML异种移植物的存活（p= 0.001）。然而，呼肠孤病毒诱导的AKT、应激活化蛋白激酶/c-Jun N-末端激酶（SAPK/JNK）和NF-κB信号传导的活化导致hUC-MSC的固有迁移特性的维持和促炎细胞因子（特别是CXCL 10）的分泌。在具有免疫能力的AML小鼠中，携带呼肠孤病毒的MSC引发免疫反应，并最终抑制肿瘤生长。因此，这些结果表明，骨髓间充质干细胞作为载体的溶瘤呼肠孤病毒可以增强病毒治疗的抗肿瘤疗效。
Chemotherapy is the main treatment for acute myeloid leukemia (AML), but the therapeutic efficacy is modest, and most commonly manifests as relapse from remission. Thus, improving long-term AML survival is a crucial clinical challenge. In recent years, oncolytic virotherapy has provided an alternative approach for AML treatment. The use of oncolytic reoviruses has been explored in more than 30 clinical trials for safety and feasibility issues. However, like other oncolytic viruses, neutralizing antibodies (NAbs) reduce therapeutic efficacy. To tackle this problem, human umbilical cord mesenchymal stem cells (hUC-MSCs) were used to deliver reovirus usingin vitroandin vivomodels. Human UC-MSCs were successfully loaded with reovirus, without impairing biological function. We also observedin vitroprotective effects of hUC-MSCs on reovirus in the presence of NAbs. In the immunocompromised AML mouse model, hUC-MSCs effectively carried reoviruses to tumor lesions and significantly prolonged the survival of AML xenografts in mice in the presence of a high titer anti-reovirus antibody (p= 0.001). However, reovirus-induced activation of AKT, stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and NF-κB signaling led to the maintenance of intrinsic migratory properties and secretion of pro-inflammatory cytokines from hUC-MSCs, particularly CXCL10. In immuno-competent AML mice, MSCs carrying reovirus triggered immune responses, and eventually inhibited tumor growth. Therefore, these results suggest that MSCs as carriers of oncolytic reoviruses can enhance the antitumor efficacy of virotherapy.