Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
J Transl Med. 2010 Jan 27;8:7. doi: 10.1186/1479-5876-8-7.
The conventional treatment protocol in high-intensity focused ultrasound (HIFU) therapy utilizes a dense-scan strategy to produce closely packed thermal lesions aiming at eradicating as much tumor mass as possible. However, this strategy is not most effective in terms of inducing a systemic anti-tumor immunity so that it cannot provide efficient micro-metastatic control and long-term tumor resistance. We have previously provided evidence that HIFU may enhance systemic anti-tumor immunity by in situ activation of dendritic cells (DCs) inside HIFU-treated tumor tissue. The present study was conducted to test the feasibility of a sparse-scan strategy to boost HIFU-induced anti-tumor immune response by more effectively promoting DC maturation.
An experimental HIFU system was set up to perform tumor ablation experiments in subcutaneous implanted MC-38 and B16 tumor with dense- or sparse-scan strategy to produce closely-packed or separated thermal lesions. DCs infiltration into HIFU-treated tumor tissues was detected by immunohistochemistry and flow cytometry. DCs maturation was evaluated by IL-12/IL-10 production and CD80/CD86 expression after co-culture with tumor cells treated with different HIFU. HIFU-induced anti-tumor immune response was evaluated by detecting growth-retarding effects on distant re-challenged tumor and tumor-specific IFN-gamma-secreting cells in HIFU-treated mice.
HIFU exposure raised temperature up to 80 degrees centigrade at beam focus within 4 s in experimental tumors and led to formation of a well-defined thermal lesion. The infiltrated DCs were recruited to the periphery of lesion, where the peak temperature was only 55 degrees centigrade during HIFU exposure. Tumor cells heated to 55 degrees centigrade in 4-s HIFU exposure were more effective to stimulate co-cultured DCs to mature. Sparse-scan HIFU, which can reserve 55 degrees-heated tumor cells surrounding the separated lesions, elicited an enhanced anti-tumor immune response than dense-scan HIFU, while their suppressive effects on the treated primary tumor were maintained at the same level. Flow cytometry analysis showed that sparse-scan HIFU was more effective than dense-scan HIFU in enhancing DC infiltration into tumor tissues and promoting their maturation in situ.
Optimizing scan strategy is a feasible way to boost HIFU-induced anti-tumor immunity by more effectively promoting DC maturation.
高强度聚焦超声（HIFU）治疗的传统治疗方案利用密集扫描策略产生紧密堆积的热损伤，旨在尽可能消除尽可能多的肿瘤组织。然而，从诱导全身抗肿瘤免疫的角度来看，这种策略并不是最有效的，因此它不能提供有效的微转移控制和长期肿瘤抵抗。我们之前已经证明，HIFU 可以通过原位激活 HIFU 治疗的肿瘤组织内的树突状细胞（DC）来增强全身抗肿瘤免疫。本研究旨在测试稀疏扫描策略的可行性，通过更有效地促进 DC 成熟来增强 HIFU 诱导的抗肿瘤免疫反应。
建立了一个实验性 HIFU 系统，以在皮下植入的 MC-38 和 B16 肿瘤中进行肿瘤消融实验，采用密集或稀疏扫描策略产生紧密或分离的热损伤。通过免疫组织化学和流式细胞术检测 DC 浸润到 HIFU 治疗的肿瘤组织中。通过与不同 HIFU 处理的肿瘤细胞共培养后产生的 IL-12/IL-10 产率和 CD80/CD86 表达来评估 DC 成熟。通过检测远处再挑战肿瘤的生长抑制作用和 HIFU 治疗小鼠中肿瘤特异性 IFN-γ分泌细胞来评估 HIFU 诱导的抗肿瘤免疫反应。
实验性肿瘤中，HIFU 在 4 秒内将温度升高到 80 摄氏度，在焦点处产生明确的热损伤。浸润的 DC 被募集到损伤的外围，在 HIFU 暴露期间，那里的峰值温度仅为 55 摄氏度。在 4 秒 HIFU 暴露下加热至 55 摄氏度的肿瘤细胞更有效地刺激共培养的 DC 成熟。稀疏扫描 HIFU 可以保留分离损伤周围的 55 摄氏度加热的肿瘤细胞，引发比密集扫描 HIFU 更强的抗肿瘤免疫反应，同时保持对治疗原发性肿瘤的抑制作用处于相同水平。流式细胞术分析表明，稀疏扫描 HIFU 比密集扫描 HIFU 更有效地增强 DC 浸润到肿瘤组织中，并促进其原位成熟。
优化扫描策略是通过更有效地促进 DC 成熟来增强 HIFU 诱导的抗肿瘤免疫的可行方法。
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