Department of Ultrasound, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
Ultrasound Molecular Imaging Joint Laboratory of Heilongjiang Province, Harbin, Heilongjiang Province, China.
Cancer Immunol Immunother. 2024 Jan 18;73(1):15. doi: 10.1007/s00262-023-03590-5.
Immune checkpoint inhibitors (ICIs) have transformed traditional cancer treatments. Specifically, ICI-related myocarditis is an immune-related adverse event (irAE) with high mortality. ICIs activate CD4 T-lymphocyte reprogramming, causing an imbalance between Th17 and Treg cell differentiation, ultimately leading to myocardial inflammatory damage. Low-intensity pulsed ultrasound (LIPUS) can limit inflammatory responses, with positive therapeutic effects across various cardiovascular inflammatory diseases; however, its role in the pathogenesis of ICI-related myocarditis and CD4 T-cell dysfunction remains unclear. Accordingly, this study investigated whether LIPUS can alleviate ICI-related myocarditis inflammatory damage and, if so, aimed to elucidate the beneficial effects of LIPUS and its underlying molecular mechanisms.
An in vivo model of ICI-related myocarditis was obtained by intraperitonially injecting male A/J mice with an InVivoPlus anti-mouse PD-1 inhibitor. LIPUS treatment was performed via an ultrasound-guided application to the heart via the chest wall. The echocardiographic parameters were observed and cardiac function was assessed using an in vivo imaging system. The expression of core components of the HIPPO pathway was analyzed via western blotting.
LIPUS treatment reduced cardiac immune responses and inflammatory cardiac injury. Further, LIPUS treatment alleviated the inflammatory response in mice with ICI-related myocarditis. Mechanistically, in the HIPPO pathway, the activation of Mst1-TAZ axis improved autoimmune inflammation by altering the interaction between the transcription factors FOXP3 and RORγt and regulating the differentiation of Treg and Th17 cells.
LIPUS therapy was shown to reduce ICI-related myocarditis inflammatory damage and improve cardiac function, representing an exciting finding for irAEs treatment.
免疫检查点抑制剂（ICI）改变了传统的癌症治疗方法。具体而言，ICI 相关心肌炎是一种具有高死亡率的免疫相关不良事件（irAE）。ICI 可激活 CD4 T 淋巴细胞重编程，导致 Th17 和 Treg 细胞分化失衡，最终导致心肌炎症损伤。低强度脉冲超声（LIPUS）可限制炎症反应，对多种心血管炎症性疾病均具有积极的治疗作用；然而，其在 ICI 相关心肌炎和 CD4 T 细胞功能障碍发病机制中的作用尚不清楚。因此，本研究旨在探讨 LIPUS 是否可以减轻 ICI 相关心肌炎的炎症损伤，如果可以，阐明 LIPUS 的有益作用及其潜在的分子机制。
通过腹膜内注射 InVivoPlus 抗小鼠 PD-1 抑制剂在雄性 A/J 小鼠体内建立 ICI 相关心肌炎的体内模型。通过胸壁进行超声引导应用进行 LIPUS 治疗。观察超声心动图参数并使用体内成像系统评估心脏功能。通过 Western blot 分析 HIPPO 通路的核心组成部分的表达。
LIPUS 治疗可减轻心脏免疫反应和炎症性心脏损伤。此外，LIPUS 治疗可减轻 ICI 相关心肌炎小鼠的炎症反应。机制上，在 HIPPO 通路中，通过改变转录因子 FOXP3 和 RORγt 的相互作用以及调节 Treg 和 Th17 细胞的分化，Mst1-TAZ 轴的激活改善了自身免疫炎症。
LIPUS 治疗可减轻 ICI 相关心肌炎的炎症损伤并改善心脏功能，为 irAEs 的治疗提供了令人振奋的发现。
