Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Institute of Ultrasound Imaging of Chongqing Medical University, Chongqing, China.
J Immunother Cancer. 2023 Jan;11(1). doi: 10.1136/jitc-2022-006226.
High-intensity focused ultrasound (HIFU) has shown considerable promise in treating solid tumors, but its ultrasonic energy is easily attenuated, resulting in insufficient energy accumulation in the target area. Moreover, HIFU ablation alone may inevitably lead to the presence of residual tumors, which may cause tumor recurrence and metastasis. Here, we describe a synergistic regimen combining HIFU facilitation with immunomodulation based on a novel oxygen-carrying biomimetic perfluorocarbon nanoparticle (M@P-SOP) to stimulate immunogenic cell death in tumor cells while alleviating immune suppression tumor microenvironment.
M@P-SOP was prepared by double emulsion and film extrusion method. The anticancer and antimetastatic effects of M@P-SOP were evaluated on a preclinical transplanted 4T1 tumor model by combining HIFU and immunotherapy. Flow cytometry and immunofluorescence were used to clarify the potential mechanism of HIFU+M@P-SOP and their role in anti-programmed death ligand-1 (PD-L1) therapy.
Guided by photoacoustic/MR/ultrasound (US) multimodal imaging, M@P-SOP was abundantly enriched in tumor, which greatly enhanced HIFU's killing of tumor tissue in situ, induced stronger tumor immunogenic cell death, stimulated dendritic cell maturation and activated CD8 T cells. At the same time, M@P-SOP released oxygen to alleviate the tumor hypoxic environment, repolarizing the protumor M2-type macrophages into antitumor M1-type. With concurrent anti-PD-L1 treatment, the antitumor immune response was further amplified to the whole body, and the growth of mimic distant tumor was effectively suppressed.
Our findings offer a highly promising HIFU synergist for effectively ameliorating acoustic and hypoxia environment, eventually inhibiting tumor growth and metastasis by stimulating host's antitumor immunity under HIFU ablation, especially in synergizing with PD-L1 antibody immunotherapy.
高强度聚焦超声（HIFU）在治疗实体瘤方面显示出巨大的潜力，但它的超声能量容易衰减，导致目标区域的能量积累不足。此外，单独使用 HIFU 消融不可避免地会导致残留肿瘤的存在，这可能导致肿瘤复发和转移。在这里，我们描述了一种联合高强度聚焦超声促进与免疫调节的协同方案，该方案基于一种新型载氧仿生全氟碳纳米颗粒（M@P-SOP），以刺激肿瘤细胞的免疫原性细胞死亡，同时缓解免疫抑制肿瘤微环境。
M@P-SOP 通过双乳液和薄膜挤压法制备。通过将 HIFU 与免疫治疗相结合，在临床前移植的 4T1 肿瘤模型上评估 M@P-SOP 的抗癌和抗转移作用。流式细胞术和免疫荧光用于阐明 HIFU+M@P-SOP 的潜在机制及其在抗程序性死亡配体-1（PD-L1）治疗中的作用。
在光声/MR/超声（US）多模态成像的指导下，M@P-SOP 在肿瘤中大量富集，极大地增强了 HIFU 原位杀伤肿瘤组织的能力，诱导更强的肿瘤免疫原性细胞死亡，刺激树突状细胞成熟并激活 CD8 T 细胞。同时，M@P-SOP 释放氧气以缓解肿瘤缺氧环境，将促肿瘤 M2 型巨噬细胞重编程为抗肿瘤 M1 型。同时进行抗 PD-L1 治疗，进一步放大了抗肿瘤免疫反应，有效地抑制了模拟远处肿瘤的生长。
我们的研究结果为 HIFU 提供了一种很有前途的增效剂，可在 HIFU 消融下通过刺激宿主的抗肿瘤免疫来有效改善声学和缺氧环境，最终抑制肿瘤生长和转移，尤其是与 PD-L1 抗体免疫治疗协同作用时。
