利用组织碎化技术调节肿瘤微环境并改善全身抗肿瘤免疫反应:神奇气泡。
Magic bubbles: utilizing histotripsy to modulate the tumor microenvironment and improve systemic anti-tumor immune responses.
发表日期:2023
作者:
Khan M Imran, Anutosh Ganguly, Tamalika Paul, Manali Powar, Eli Vlaisavljevich, Clifford S Cho, Irving C Allen
来源:
Cell Death & Disease
摘要:
聚焦超声(FUS)作为治疗癌症的一种有前途的主要和辅助疗法正逐渐兴起。其中包括组织碎化术,这是一种无创、非电离辐射、非热超声引导消融疗法。随着组织碎化术从实验室走向临床应用,已经明显看到这种疗法在局部肿瘤消融之外还有其他益处。具体而言,组织碎化术具有将局部肿瘤微环境从免疫“冷”转变为“热”的潜力。这与损伤相关的分子模式的产生、选择性促炎介质的释放以及在治疗区域外细胞中诱导炎症性细胞死亡有关。除了诱导这种先天免疫反应外,组织碎化术还可以改善适应性免疫系统的参与,并促进针对远处肿瘤和转移病灶的系统性抗肿瘤免疫。这些令人着迷的观察表明,在广泛转移的疾病负担下,有选择性地对一部分可以接触到的肿瘤进行组织碎化术可能是最大程度提高对系统免疫治疗的响应性的一种方式。显然还需要更多的工作来优化最佳组织碎化术参数与先天和适应性免疫反应的相互作用的治疗策略。同样,还需要严格的临床研究来验证这些现象在人类患者中的存在性和重复性。随着这项技术接近获得临床使用的审批,我们期望本综述中总结的认识和免疫调节机制能作为理性临床研究的指导,验证和优化组织碎化术肿瘤消融在免疫治疗中的潜在作用。
Focused Ultrasound (FUS) is emerging as a promising primary and adjunct therapy for the treatment of cancer. This includes histotripsy, which is a noninvasive, non-ionizing, non-thermal ultrasound guided ablation modality. As histotripsy has progressed from bench-to-bedside, it has become evident that this therapy has benefits beyond local tumor ablation. Specifically, histotripsy has the potential to shift the local tumor microenvironment from immunologically 'cold' to 'hot'. This is associated with the production of damage associated molecular patterns, the release of a selection of proinflammatory mediators, and the induction of inflammatory forms of cell death in cells just outside of the treatment zone. In addition to the induction of this innate immune response, histotripsy can also improve engagement of the adaptive immune system and promote systemic anti-tumor immunity targeting distal tumors and metastatic lesions. These tantalizing observations suggest that, in settings of widely metastatic disease burden, selective histotripsy of a limited number of accessible tumors could be a means of maximizing responsiveness to systemic immunotherapy. More work is certainly needed to optimize treatment strategies that best synergize histotripsy parameters with innate and adaptive immune responses. Likewise, rigorous clinical studies are still necessary to verify the presence and repeatability of these phenomena in human patients. As this technology nears regulatory approval for clinical use, it is our expectation that the insights and immunomodulatory mechanisms summarized in this review will serve as directional guides for rational clinical studies to validate and optimize the potential immunotherapeutic role of histotripsy tumor ablation.