Peritumoral administration of IFNβ upregulated mesenchymal stem cells inhibits tumor growth in an orthotopic, immunocompetent rat glioma model
Peritumoral administration of IFNβ upregulated mesenchymal stem cells inhibits tumor growth in an orthotopic, immunocompetent rat glioma model
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瘤周给予 IFNβ 上调的间充质干细胞可抑制原位、免疫活性大鼠神经胶质瘤模型中的肿瘤生长
DOI：
10.1136/jitc-2019-000164
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发表时间：
2020-01-01
影响因子：
10.9
通讯作者：
Shen, Jun
中科院分区：
文献类型：
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作者：
Mao, Jiaji;Cao, Minghui;Shen, Jun
IFN β免疫疗法是治疗恶性胶质瘤的一种很有前途的策略。然而，由于肿瘤内干扰素β浓度低和主要的不良反应，全身给药是不充分的。本研究旨在通过体内MRI跟踪确定间充质干细胞（MSCs）是否可以作为细胞载体局部递送IFN β用于胶质瘤治疗。方法构建IFN β和铁蛋白重链（FTH）报告基因重组慢病毒载体，转染MSCs。评估转导的有效性和安全性。将IFN β和FTH过表达的MSCs （IFN β -FTH-MSCs）通过瘤周、脑内、瘤内或动脉内注射移植到颅内颅正位大鼠F98胶质瘤后，通过组织学分析、定量PCR和ELISA检测，MRI追踪IFN β -FTH-MSCs，并评估其在体内对胶质瘤的治疗效果。结果构建的慢病毒能有效、安全地诱导smsc上调IFN β分泌和FTH表达。在瘤周注射IFN β - fth - mscs后，MRI上显示为低信号，逐渐减弱，但直到11天仍然可见。与其他给药途径相比，仅瘤周注射IFN β - fth - mscs对胶质瘤生长有显著的抑制作用。近30%的IFN β - fth - mscs在瘤周注射后存活长达11天，而通过其他途径注射的IFN β - fth - mscs在11天内大部分死亡。瘤周移植的IFN β - fth - mscs持续分泌IFN β，导致胶质瘤内明显的Batf3（+）树突状细胞和CD8(+) T淋巴细胞浸润。结论smscs可作为IFN β的细胞载体，通过瘤周注射治疗恶性胶质瘤。
BackgroundImmunotherapy with IFN beta is a promising strategy for treating malignant glioma. However, systemic administration of IFN beta is inadequate because of low intratumoral concentration and major adverse effects. This study aimed to determine whether mesenchymal stem cells (MSCs) can be used as cellular vehicles to locally deliver IFN beta for glioma therapy by using in vivo MRI tracking.MethodsA recombinant lentiviral vector encoding IFN beta and ferritin heavy chain (FTH) reporter genes was constructed to transduce MSCs. The effectiveness and safety of transduction were assessed. After the IFN beta and FTH overexpressed MSCs (IFN beta-FTH-MSCs) were transplanted into intracranial orthotopic rat F98 gliomas via peritumoral, intracerebral, intratumoral or intra-arterial injection, MRI was performed to track IFN beta-FTH-MSCs and to evaluate their therapeutic effect on glioma in vivo, as validated by histologic analysis, quantitative PCR and ELISA assays.ResultsMSCs were efficiently and safely transduced to upregulate their IFN beta secretion and FTH expression by the constructed lentivirus. After peritumoral injection, IFN beta-FTH-MSCs appeared as hypointense signals on MRI, which gradually diminished but remained visible until 11 days. Compared with other administration routes, only peritumoral injection of IFN beta-FTH-MSCs showed a remarkable inhibition on the glioma growth. Nearly 30% of IFN beta-FTH-MSCs survived up to 11 days after peritumoral injection, while most of IFN beta-FTH-MSCs injected via other routes died within 11 days. IFN beta-FTH-MSCs grafted peritumorally secreted IFN beta persistently, leading to pronounced Batf3(+) dendritic cells and CD8(+) T lymphocyte infiltration within the glioma.ConclusionsMSCs can be used as cellular vehicles of IFN beta to treat malignant glioma effectively via peritumoral injection.