Hu Zhenlin, Yang Xiao Yi, Liu Yunbo, Sankin Georgy N, Pua Eric C, Morse Michael A, Lyerly H Kim, Clay Timothy M, Zhong Pei
Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC 27708, USA.
J Transl Med. 2007 Jul 11;5:34. doi: 10.1186/1479-5876-5-34.
BACKGROUND: High intensity focused ultrasound (HIFU) is an emerging non-invasive treatment modality for localized treatment of cancers. While current clinical strategies employ HIFU exclusively for thermal ablation of the target sites, biological responses associated with both thermal and mechanical damage from focused ultrasound have not been thoroughly investigated. In particular, endogenous danger signals from HIFU-damaged tumor cells may trigger the activation of dendritic cells. This response may play a critical role in a HIFU-elicited anti-tumor immune response which can be harnessed for more effective treatment. METHODS: Mice bearing MC-38 colon adenocarcinoma tumors were treated with thermal and mechanical HIFU exposure settings in order to independently observe HIFU-induced effects on the host's immunological response. In vivo dendritic cell activity was assessed along with the host's response to challenge tumor growth. RESULTS: Thermal and mechanical HIFU were found to increase CD11c+ cells 3.1-fold and 4-fold, respectively, as compared to 1.5-fold observed for DC injection alone. In addition, thermal and mechanical HIFU increased CFSE+ DC accumulation in draining lymph nodes 5-fold and 10-fold, respectively. Moreover, focused ultrasound treatments not only caused a reduction in the growth of primary tumors, with tumor volume decreasing by 85% for thermal HIFU and 43% for mechanical HIFU, but they also provided protection against subcutaneous tumor re-challenge. Further immunological assays confirmed an enhanced CTL activity and increased tumor-specific IFN-gamma-secreting cells in the mice treated by focused ultrasound, with cytotoxicity induced by mechanical HIFU reaching as high as 27% at a 10:1 effector:target ratio. CONCLUSION: These studies present initial encouraging results confirming that focused ultrasound treatment can elicit a systemic anti-tumor immune response, and they suggest that this immunity is closely related to dendritic cell activation. Because DC activation was more pronounced when tumor cells were mechanically lysed by focused ultrasound treatment, mechanical HIFU in particular may be employed as a potential strategy in combination with subsequent thermal ablations for increasing the efficacy of HIFU cancer treatment by enhancing the host's anti-tumor immunity.
背景：高强度聚焦超声（HIFU）是一种新兴的用于癌症局部治疗的非侵入性治疗方式。虽然目前的临床策略仅将HIFU用于靶位点的热消融，但聚焦超声产生的热损伤和机械损伤所引发的生物学反应尚未得到充分研究。特别是，HIFU损伤的肿瘤细胞产生的内源性危险信号可能会触发树突状细胞的激活。这种反应可能在HIFU引发的抗肿瘤免疫反应中起关键作用，而该免疫反应可用于更有效的治疗。 方法：对携带MC-38结肠腺癌肿瘤的小鼠进行热和机械HIFU照射，以独立观察HIFU对宿主免疫反应的影响。评估体内树突状细胞活性以及宿主对挑战肿瘤生长的反应。 结果：与单独注射树突状细胞时观察到的1.5倍相比，热HIFU和机械HIFU分别使CD11c+细胞增加3.1倍和4倍。此外，热HIFU和机械HIFU分别使引流淋巴结中CFSE+树突状细胞的积累增加5倍和10倍。此外，聚焦超声治疗不仅使原发性肿瘤的生长减缓，热HIFU使肿瘤体积减少85%，机械HIFU使肿瘤体积减少43%，而且还提供了针对皮下肿瘤再次攻击的保护作用。进一步的免疫分析证实，聚焦超声治疗的小鼠中CTL活性增强，肿瘤特异性分泌IFN-γ的细胞增加，在效应细胞与靶细胞比例为10:1时，机械HIFU诱导的细胞毒性高达27%。 结论：这些研究给出了初步的令人鼓舞的结果，证实聚焦超声治疗可引发全身性抗肿瘤免疫反应，并且表明这种免疫与树突状细胞激活密切相关。由于在通过聚焦超声治疗机械裂解肿瘤细胞时树突状细胞的激活更为明显，特别是机械HIFU可作为一种潜在策略，与后续的热消融联合使用，通过增强宿主的抗肿瘤免疫力来提高HIFU癌症治疗的疗效。
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