替莫唑胺联合声动力学疗法诱导脑胶质瘤发生免疫原性细胞死亡。
Temozolomide-based sonodynamic therapy induces immunogenic cell death in glioma.
机构信息
Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin 300350, China.
College of Environmental Science and Engineering of Nankai University, Tianjin 300350, China.
出版信息
Clin Immunol. 2023 Nov;256:109772. doi: 10.1016/j.clim.2023.109772. Epub 2023 Sep 15.
BACKGROUND
In our previous study, we found for the first time that temozolomide (TMZ), the first-line chemotherapeutic agent for glioblastoma (GBM), can generate a large amount of reactive oxygen species (ROS) under ultrasound irradiation. Sonodynamic therapy (SDT) using TMZ as the sonosensitizer produced more potent antitumor effects than TMZ alone. Here, we further evaluate the effects of TMZ-based SDT on subcellular structures and investigate the immunogenic cell death (ICD)-inducing capability of TMZ-based SDT.
METHODS
The sonotoxic effects of TMZ were explored in LN229 and GL261 glioma cells. The morphology of endoplasmic reticulum and mitochondria was observed by transmission electron microscopy. The nuclear DNA damage was represented by γ-H2AX staining. Bone marrow-derived dendritic cells (BMDCs) were employed to assess ICD-inducing capability of TMZ-based SDT. A cyclic arginine-glycine-aspartic (c(RGDyC))-modified nanoliposome drug delivery platform was used to improve the tumor targeting of SDT.
RESULTS
TMZ-based SDT had a greater inhibitory effect on glioma cells than TMZ alone. Transmission electron microscopy revealed that TMZ-based SDT caused endoplasmic reticulum dilation and mitochondrial swelling. In addition, endoplasmic reticulum stress response (ERSR), nuclear DNA damage and mitochondrial permeability transition pore (mPTP) opening were promoted in TMZ-based SDT group. Most importantly, we found that TMZ-based SDT could promote the "danger signals" produced by glioma cells and induce the maturation and activation of BMDCs, which was associated with the mitochondrial DNA released into the cytoplasm in glioma cells. In vivo experiments showed that TMZ-based SDT could remodel glioma immune microenvironment and provoke durable and powerful anti-tumor immune responses. What's more, the engineered nanoliposome vector of TMZ conferred SDT tumor targeting, providing an option for safer clinical application of TMZ in combination with SDT in the future.
CONCLUSIONS
TMZ-based SDT was capable of triggering ICD in glioma. The discovery of TMZ as a sonosensitizer have shown great promise in the treatment of GBM.
背景
在我们之前的研究中，我们首次发现替莫唑胺（TMZ），胶质母细胞瘤（GBM）的一线化疗药物，在超声辐射下会产生大量活性氧（ROS）。使用 TMZ 作为声敏剂的声动力学疗法（SDT）比单独使用 TMZ 产生更强的抗肿瘤效果。在这里，我们进一步评估了基于 TMZ 的 SDT 对亚细胞结构的影响，并研究了基于 TMZ 的 SDT 的免疫原性细胞死亡（ICD）诱导能力。
方法
在 LN229 和 GL261 神经胶质瘤细胞中探索 TMZ 的声毒性作用。通过透射电子显微镜观察内质网和线粒体的形态。γ-H2AX 染色代表核 DNA 损伤。骨髓来源的树突状细胞（BMDCs）用于评估基于 TMZ 的 SDT 的 ICD 诱导能力。使用循环精氨酸-甘氨酸-天冬氨酸（c（RGDyC））修饰的纳米脂质体药物递送平台来提高 SDT 的肿瘤靶向性。
结果
与单独使用 TMZ 相比，基于 TMZ 的 SDT 对神经胶质瘤细胞具有更强的抑制作用。透射电子显微镜显示，基于 TMZ 的 SDT 导致内质网扩张和线粒体肿胀。此外，基于 TMZ 的 SDT 促进内质网应激反应（ERSR）、核 DNA 损伤和线粒体通透性转换孔（mPTP）开放。最重要的是，我们发现基于 TMZ 的 SDT 可以促进胶质瘤细胞产生的“危险信号”，并诱导 BMDCs 的成熟和激活，这与胶质瘤细胞中线粒体 DNA 释放到细胞质有关。体内实验表明，基于 TMZ 的 SDT 可以重塑胶质瘤免疫微环境，引发持久而强大的抗肿瘤免疫反应。更重要的是，TMZ 基于的纳米脂质体载体赋予了 SDT 肿瘤靶向性，为未来 TMZ 联合 SDT 的更安全的临床应用提供了一种选择。
结论
基于 TMZ 的 SDT 能够在神经胶质瘤中触发 ICD。TMZ 作为声敏剂的发现为胶质母细胞瘤的治疗带来了很大的希望。
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