Effect of different MRgHIFU approaches on anti-tumor responses

 描述（由申请人提供）：高强度聚焦超声（HIFU）已成为一种新的和有前途的治疗模式，用于各种癌症。MRI引导的高强度聚焦超声（MRgHIFU）允许对几乎所有内脏器官中的组织块进行非手术精确消融。MRgHIFU在治疗患有不可切除的癌症或身体条件差的手术患者方面具有优势。此外，与放疗和化疗不同，HIFU可以重复应用而不会累积全身毒性。HIFU有3种主要的大规模消融方法：（i）连续波消融，快速导致高温（>60°C）、组织坏死凝固和蛋白质变性;（ii）脉冲波消融，导致组织坏死和蛋白质变性。 高温（≤50°C）和热应激诱导的细胞凋亡，和（iii）组织破坏，机械破坏而不改变温度。目前的抗癌方法使用高热消融，因为它们的目标是最短的治疗时间以完成肿瘤消融。虽然这种方法消除了靶向肿瘤，但它不一定导致消除转移和预防复发所需的适应性抗肿瘤反应的发展。适应性抗肿瘤应答的诱导需要DC摄取垂死/死亡的肿瘤细胞，然后在刺激性环境中将肿瘤抗原呈递给CD 8+和CD 4 + T细胞。垂死/死亡细胞的摄取通常是致耐受性过程，以防止在正常组织更新时发生自身免疫应答。然而，特定类型的细胞死亡导致不同的死亡相关分子模式（DAMP）的释放，其作用于DC并灌输免疫刺激表型并促进T细胞引发细胞相关抗原。很可能3种HIFU方法对DAMP和肿瘤抗原的稳定性、构型和释放具有不同的影响。然而，目前还没有关于3种不同的HIFU方法如何影响适应性抗肿瘤反应的发展的信息。本申请的总体目标是对不同MRgHIFU治疗后对热稳定和热不稳定肿瘤抗原的适应性反应的发展进行定量和定性分析，可用于优化不同临床环境中的HIFU策略。我们将使用体内肿瘤消融模型来确定不同MRgHIFU方法对肿瘤特异性CD 8+和CD 4 + T细胞的大小、表型、多功能性、记忆发育和保护能力的影响。由于许多（如果不是大多数）HIFU方案仍在开发中，我们的临床前研究结果具有很高的转化潜力，因为它们将为MRgHFU治疗的设计提供第一个免疫学循证依据。此外，它们将提供对适应性反应的动力学的洞察，其可用于确定组合治疗（例如免疫检查点干扰或额外化疗）的最有效窗口。

 DESCRIPTION (provided by applicant): High intensity focused ultrasound (HIFU) has emerged as a new and promising treatment modality for a broad variety of cancers. MRI-guided HIFU (MRgHIFU) allows for the non-surgical, precise ablation of tissue masses in almost all internal organs. MRgHIFU is advantageous in treating patients with unresectable cancers or with poor physical condition for surgery. Moreover, unlike radiation and chemotherapy, HIFU can be applied repetitively without accumulating systemic toxicity. HIFU has 3 main approaches for mass ablation: (i) continuous-wave ablation, rapidly resulting in high temperatures (>60°C), necrotic coagulation of the tissue, and protein denaturation; (ii) pulsed-wave ablation, leading to hyperthermia (≤50°C) and heat-stress induced apoptosis, and (iii) histotripsy, mechanical disruption without changes in temperature. Current anti-cancer approaches use high-heat ablation as they aim for the shortest treatment time for complete tumor ablation. While this approach eliminates the targeted tumor, it does not necessarily result in the development of adaptive antitumor responses that are required for the elimination of metastases and prevention of recurrences. Induction of adaptive anti-tumor responses requires the uptake of dying/dead tumor cells by DCs followed by tumor antigen presentation to both CD8+ and CD4+ T cells in a stimulatory context. Uptake of dying/dead cells is generally a tolerogenic process in order to prevent development of autoimmune response upon normal tissue turnover. However, specific types of cell death result in the release of distinct Death Associated Molecular Patterns (DAMPs) that act on DCs and instill an immunostimulatory phenotype and promote T cell priming to cell-associated antigens. It is likely that the 3 HIFU approaches have distinct effects on the stability, configuration, and release of both the DAMPs and tumor antigens. However, there is currently is no information how the 3 different HIFU approaches affect the development of the adaptive anti-tumor response. The overall objective of this application is to generate quantitative and qualitative insight into the development of adaptive responses to heat-stable and heat-labile tumor antigens after different MRgHIFU treatments that can be used to optimize HIFU strategies in different clinical settings. We will use an in vivo tumor ablation model to determine the effect of different MRgHIFU approaches on the magnitude, phenotype, polyfunctionality, memory development, and protective capacity of tumor-specific CD8+ and CD4+ T cells. As many, if not most, HIFU protocols are still under development, the outcomes of our pre-clinical studies have high translational potential as they will provide the first immunological evidence-based rationale for the design of MRgHFU treatments. Moreover, they will provide insight into the kinetics of the adaptive response that can be used to determine the most efficacious window for combinational treatments such as immune- checkpoint interference or additional chemotherapy.