超声介导的肿瘤免疫治疗

Ultrasound induced cancer immunotherapy

免疫治疗是一种新兴的肿瘤疗法.与传统的疗法直接杀伤肿瘤不同,免疫治疗是通过激活或增强人体免疫系统,依靠自身免疫功能间接杀灭癌细胞和肿瘤组织的疗法.考虑到肿瘤的异质性和遗传不稳定性,单一的疗法不能达到完全治愈肿瘤的效果.近年来,有研究表明,利用超声可以提高机体对肿瘤的免疫反应强度,加强肿瘤的免疫治疗效果.聚焦超声在破坏肿瘤的同时可以导致机体在原位产生肿瘤碎片和肿瘤相关抗原等物质,增强肿瘤的免疫原性,刺激细胞免疫,诱导机体产生免疫应答.微泡是临床上使用的超声造影剂,微泡的加入可以加强聚焦超声对肿瘤的破坏效果,引发更强的免疫反应.利用超声和微泡的组合还可以打开血脑屏障,促进免疫细胞或免疫治疗药物进入血脑屏障发挥作用.此外,微泡还是一种常用的基因和药物载体,利用超声将负载免疫相关基因或抗原的微泡递送到肿瘤细胞或免疫细胞中,同样可以增强免疫应答反应,提高肿瘤免疫治疗的疗效.

Cancer immunotherapy is rapidly becoming one of the pillars of anti-cancer therapy. Unlike previous cancer therapies, immunotherapy aims at activating or enhancing the natural immune response of the patient to kill cancer cells and tis- sues. It means that the immune system can be activated to attack the cancer cells but leaving the normal, healthy cells intact. Immunotherapy can be realised in several treatment approaches, such as the increase of the non-specific immune system, by cancer vaccines, adoptive cell transfer and monoclonal antibodies. Considering the heterogenicity and genetic instability of tumors, a certain kind of treatment may not achieve ideal therapeutic effect all the time. In recent years, using ultrasound to achieve immune response towards cancer shows great promise. Ultrasound is one of the most com- monly used imaging diagnostic techniques for cancer diseases. Besides, ultrasound has attraction for both direct US treatment and activating drug delivery due to its biological effects. Several studies suggest that ultrasound can be used to boost the host anti-tumor immune responses. The recent advances, the potential and existing problems of US induced cancer immunotherapy are reviewed. Focused ultrasound （FUS） can achieve a high US energy with in a small focal volume, which causes local destruction of tumor tissues with minimal damage to surrounding normal tissues. Destruction of tumors caused by FUS may lead to generate tumor debris and tumor-associated antigens （TAAs） in situ, which can facilitate and amplify the anti-tumor im- mune responses, and protect the body from tumorgenesis when re-challenged. HIFU also has effects on other than the destruction of the tissue. HIFU treatment, which triggers a Thl type response, leads to significant changes in cell-mediated immunity. HIFU treatment also acts by balancing the cancer-induced immuno-suppression in tumor mi- cro-environment. Microbubbles （MBs）, a kind of US contrast agents, can improve the therapeutic efficacy of FUS because of their in- tensity reflection and scattering of ultrasonic waves, which shows great value in clinical use. The addition of MBs to FUS can help generate more local destruction in the area of focus. Combination FUS with microbubbles has been found to increase the permeability of the blood-brain barrier （BBB） and provide a temporary and targeted opening of the BBB without inflicting brain damage or inflammation, thus is an attractive means to deliver immune cells and drugs. Sonoporation is the use of sound （typically ultrasonic frequencies） for modifying the permeability of the cell plasma membrane. Sonoporation employs the acoustic cavitation of microbubbles to enhance delivery of large molecules. This technique is usually used in gene therapy and drug delivery. Another way to achieve anti-tumor immune responses is using US and MBs to deliver immune-stimulating substances to immune cells or tumor cells. Drug delivery that using a combination of MBs and US has been explored. Non-destructive US with or without MBs can increase the delivery of active substances including antigens and immune-stimulating genes. Combination of microbubbles with cell-targeting ligands and US provides an even more smart delivery system, therefore, the therapy is not only site specific but also cell specific. Overall, the use of US to achieve immune response towards cancer is showing promise. The field is fairly young and many mechanisms are still not fully understood, thus further researches are needed.