Immunomodulation of intracranial melanoma in response to blood-tumor barrier opening with focused ultrasound
Immunomodulation of intracranial melanoma in response to blood-tumor barrier opening with focused ultrasound
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DOI：
10.7150/thno.47983
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Price, Richard J.
中科院分区：
文献类型：
--
作者：
Curley, Colleen T.;Stevens, Aaron D.;Price, Richard J.
背景：聚焦超声 (FUS) 激活微泡 (MB)，打开血脑 (BBB) 和血肿瘤屏障 (BTB)，从而实现靶向治疗。虽然 FUS+MB 介导的 BBB 打开的影响已在正常脑组织中进行了研究，但对于颅内肿瘤尚无此类研究。随着这项技术进入临床免疫治疗试验，了解FUS+MBs如何调节肿瘤免疫微环境将变得至关重要。方法和结果：批量RNA测序显示，颅内B16F1cOVA肿瘤的FUS+MBs BTB/BBB开放（1 MHz，0.5 MPa峰值负压）增加了与促炎细胞因子和趋化因子信号传导、模式识别受体信号传导以及抗原加工和呈递相关的基因表达。流式细胞术显示脑膜中树突状细胞 (DC) 的成熟（即 CD86）增加，并且肿瘤和脑膜中 DC 的抗原负载发生改变。对于肿瘤引流淋巴结中的 DC，FUS+MB 对成熟没有影响，仅引起 MHC 呈递肿瘤衍生肽增加的趋势。 FUS+MBs 不会影响肿瘤内皮细胞粘附分子的表达和活化 T 细胞的归巢。结论：FUS+MBs 介导的 BTB/BBB 打开会引发炎症特征；然而，该反应是轻微的、短暂的，并且不太可能引起独立于免疫佐剂施用的全身反应。
Background: Focused ultrasound (FUS) activation of microbubbles (MBs) for blood-brain (BBB) and blood-tumor barrier (BTB) opening permits targeted therapeutic delivery. While the effects of FUS+MBs mediated BBB opening have been investigated for normal brain tissue, no such studies exist for intracranial tumors. As this technology advances into clinical immunotherapy trials, it will be crucial to understand how FUS+MBs modulates the tumor immune microenvironment.Methods and Results: Bulk RNA sequencing revealed that FUS+MBs BTB/BBB opening (1 MHz, 0.5 MPa peak-negative pressure) of intracranial B16F1cOVA tumors increases the expression of genes related to proinflammatory cytokine and chemokine signaling, pattern recognition receptor signaling, and antigen processing and presentation. Flow cytometry revealed increased maturation (i.e. CD86) of dendritic cells (DCs) in the meninges and altered antigen loading of DCs in both the tumor and meninges. For DCs in tumor draining lymph nodes, FUS+MBs had no effect on maturation and elicited only a trend towards increased presentation of tumor-derived peptide by MHC. Neither tumor endothelial cell adhesion molecule expression nor homing of activated T cells was affected by FUS+MBs.Conclusion: FUS+MBs-mediated BTB/BBB opening elicits signatures of inflammation; however, the response is mild, transient, and unlikely to elicit a systemic response independent of administration of immune adjuvants.