Harnessing the therapeutic potential of histotripsy focused ultrasound-induced immunogenic cancer cell death

利用组织解剖聚焦超声诱导免疫原性癌细胞死亡的治疗潜力

• 批准号: 10654919
• 负责人: Clifford Cho
• 金额: $ 42.03万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654919
• 关键词: Ablation; Abscopal effect; Antigen-Presenting Cells; Antigens; Attention; CD8-Positive T-Lymphocytes; Cancer and Suicide; Cell Communication; Cell Death; Cells; Cessation of life; Clinical; Colon Carcinoma; Data; Detection; Distant; Event; Focused Ultrasound; Focused Ultrasound Therapy; Foundations; Future; Heating; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunologic Stimulation; Immunology; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Infiltration; Inflammation; Inflammatory; Intervention; Investigation; Ionizing radiation; Length; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Mechanics; Mediating; Metabolic; Modality; Pathway interactions; Patients; Physiologic pulse; Process; Radiation; Role; Series; Signal Transduction; Site; T cell infiltration; T-Cell Depletion; Technology; Testing; Therapeutic; Thermal Ablation Therapy; Tissues; Translating; Tumor Antigens; Ultrasonic wave; Work; adaptive immune response; adaptive immunity; anti-tumor immune response; cancer cell; cancer immunotherapy; carcinogenesis; cell killing; cell suicide; checkpoint inhibition; clinical practice; clinically relevant; cytotoxicity; immunogenic; immunogenic cell death; immunogenicity; inhibitor; insight; melanoma; millimeter; mouse model; multidisciplinary; neoplastic cell; new technology; pre-clinical; preservation; traditional therapy; tumor; tumor ablation

PROJECT SUMMARY/ABSTRACT Immunotherapy can be highly effective against cancers that elicit some recognition from the immune system (e.g., melanoma), but it remains ineffectual against cancers that are largely invisible to immune detection (e.g., pancreatic cancer). Advances in cancer immunotherapy will require interventions that can make cancers more apparent to the immune system. A growing body of evidence suggests that focused ultrasound (FUS) tumor ablation could be that intervention. By non-invasively disrupting cancer cells, thermal and mechanical modes of FUS have been shown to trigger surprisingly potent immune responses against tumors. We have found that histotripsy, a non-thermal mode of mechanical FUS, stimulates a powerful and systemic anti-tumor immune response strong enough to cause abscopal regression of distant, non-ablated tumor sites – effects not generally seen with traditional therapies like radiation or thermal ablation. Histotripsy is a technology that is presently being introduced into clinical use; therefore, it will be imperative to understand the mechanistic underpinnings of histotripsy immunostimulation. Our preliminary studies point to a stepwise series of events that may explain this phenomenon. First, histotripsy causes the release of subcellular cancer cell antigens in a manner that preserves their immunogenic integrity. Second, histotripsy induces cancer cells to undergo a specific pathway of cellular suicide called necroptosis – a death pathway that attracts inflammation and immune attention, effectively priming the immune system to recognize cancer antigens. What follows is a progressive infiltration of CD8+ T cells into distant tumors that is accompanied by another pathway of cancer cell death called ferroptosis – a death pathway recently discovered to be the critical mechanism by which immunotherapy-primed CD8+ T cells kill cancer cells. In this proposal, we will retrace these steps to understand how histotripsy exerts its unusually potent immune effects. First, we will quantitatively fine-tune the parameters of histotripsy tissue cavitation that cause maximally immunogenic tumor antigen release. Next, we will focus on the early induction of necroptosis to determine if this is a necessary local precursor event on which later manifestations of histotripsy immunostimulation depend. Then, we will examine the later process of CD8+ T cell-driven ferroptosis to determine if this is the mechanism by which the distant, abscopal effects of histotripsy are mediated. Finally, we will leverage mechanistic insights gained from these investigations to develop and test potential preclinical strategies with which the effects of histotripsy on tumor antigen release, necroptosis, and ferroptosis could be maximized for cancer immunotherapy. We have assembled a multidisciplinary team with expertise in FUS, immunology and cancer immunotherapy to pursue this work, which promises to reveal insights and strategies to bring the impact of cancer immunotherapy to a wider range of patients in need of cure.

项目概要/摘要 免疫疗法可以非常有效地对抗癌症，从而引起免疫系统的识别 系统（例如黑色素瘤），但它对免疫检测基本上不可见的癌症仍然无效 （例如，胰腺癌）。癌症免疫疗法的进步将需要能够使癌症发生的干预措施 对免疫系统更明显。越来越多的证据表明聚焦超声 (FUS) 肿瘤消融可能就是这种干预措施。通过非侵入性破坏癌细胞、热力和机械力 FUS 模式已被证明能够引发令人惊讶的针对肿瘤的有效免疫反应。我们有 发现组织解剖学（机械 FUS 的一种非热模式）可激发强大的系统性抗肿瘤作用 免疫反应足够强，足以引起远处未消融肿瘤部位的远隔消退——效果不 通常在放射或热消融等传统疗法中出现。组织解剖学是一项技术 目前正在投入临床使用；因此，必须了解其机制 组织解剖免疫刺激的基础。我们的初步研究指出了一系列逐步发生的事件 可以解释这一现象。首先，组织解剖导致亚细胞癌细胞抗原的释放 保持其免疫原性完整性的方式。其次，组织解剖学诱导癌细胞经历 细胞自杀的特定途径称为坏死性凋亡——一种吸引炎症和免疫的死亡途径 注意力，有效启动免疫系统识别癌症抗原。接下来是渐进式的 CD8+ T 细胞浸润到远处的肿瘤，伴随着另一种癌细胞死亡途径，称为 铁死亡——最近发现的一种死亡途径是免疫治疗引发的关键机制 CD8+ T 细胞杀死癌细胞。 在本提案中，我们将回顾这些步骤，以了解组织解剖学如何发挥其异常强大的作用 免疫作用。首先，我们将定量微调组织解剖组织空化的参数，这些参数会导致 最大程度地释放免疫原性肿瘤抗原。接下来，我们将重点关注早期诱导坏死性凋亡 确定这是否是一个必要的局部先兆事件，随后的组织解剖学表现 免疫刺激依赖。然后，我们将研究CD8+ T细胞驱动的铁死亡的后续过程 确定这是否是组织解剖学远距离、远隔效应的介导机制。最后，我们 将利用从这些研究中获得的机制见解来开发和测试潜在的临床前 组织解剖学对肿瘤抗原释放、坏死性凋亡和铁死亡的影响的策略 最大限度地用于癌症免疫治疗。我们组建了一支具有 FUS 专业知识的多学科团队， 免疫学和癌症免疫治疗来开展这项工作，有望揭示一些见解和策略 将癌症免疫疗法的影响带给更广泛的需要治愈的患者。