纳米刀消融通过STING-IRF3激活特异性免疫增强灭瘤效应的作用及其机制研究

Irreversible electroporation (IRE) is an emerging image-guided interventional ablation applied in treatment of renal cell carcinoma (RCC). This technique has attracted intensive attention with the tumors eradicated and the critical structures like renal tubulars preserved simultaneously. Ablative therapy is proposed to be difficult to completely eliminate all tumor cells, leading to a high tumor recurrence rate after ablation. Studies disclosed that ablation treatment could evoke specific immunity, however, the immunoreaction was weak and failed to provide clinical benefits. Therefore, the strategy of additional combination of adjuvants resulted from the precise immunoregulating signals might enhance the immunoactivity and help the clearance of residual cancer cells. Our preliminary data showed that IRE effectively resulted in RCC cell death accompanied with the release of numerous damage associated molecular patterns (DAMPs). The IRE-ablated zone was infiltrated with abundant dendritic cells (DCs), with the high phosphorylation levels of TBK1 and IRF3, which were the key components of STING signal, and the upregulation of effector cytokine IFN-β observed. We further found that the number of infiltrated DCs and peripheral cytotoxic T lymphocytes after IRE treatment decreased in the STING gene knockout mice. Based on these results, we speculated that IRE could activate DCs via STING signal to provoke an anti-tumor immune response. This project aims to further demonstrate the characteristics of specific anti-tumor immunity induced by IRE and the critical mechanism of maturity of DCs. Our study will provide preclinical evidence for the combination of IRE treatment and STING signal-specific adjuvants to reduce the post-ablation recurrence of RCC.

纳米刀（IRE）消融是影像引导下肾癌介入消融新技术，因可在灭瘤同时保留肾小管等重要结构而备受关注。消融治疗难以完全灭活肿瘤细胞，术后复发率高。研究发现消融可诱导特异性免疫，但反应强度弱，难以产生临床疗效。基于特异性免疫调控通路的佐剂可能增强免疫反应，有助消灭残癌。我们前期研究发现:1. IRE促使肾癌细胞死亡并释放大量损伤相关分子，伴有靶区树突状细胞（DCs）浸润和STING通路关键分子TBK1/IRF3磷酸化水平以及效应因子IFN-β表达升高; 2. STING敲除小鼠消融后DC细胞浸润及杀伤性T淋巴细胞数目减少。由此我们提出科学假设：IRE通过STING信号系统活化DC细胞，激发抗肿瘤免疫。本项目拟阐明IRE诱导特异性抗肿瘤免疫的特点及活化DC细胞的关键机制，为IRE消融联合STING信号系统特异性佐剂防治肾癌消融后复发提供临床前证据。

纳米刀消融（IRE）是影像引导下肿瘤介入消融新技术，因其可在具有独特的精确消融灭瘤同时不损伤邻近正常细胞组织、保留神经和血管结构等优点而备受关注。而传统消融治疗难以完全灭活肿瘤细胞，术后复发率高，限制了其在临床上的发展。本项目结合当前研究热点，一方面通过构建荷瘤小鼠模型，研究局部IRE 消融诱导的抗肿瘤免疫作用，发现局部IRE诱导了显着的肿瘤消退以及系统性的抗肿瘤免疫反应。我们进一步证实IFN-γ+CD8+ T细胞是抑制消融后肿瘤复发的关键因素，使用IRE处理的肿瘤细胞裂解物免疫接种小鼠可诱导长期抗肿瘤的免疫记忆反应。此外，IRE通过减少局部和脾脏的Treg和PD-1+细胞来缓解免疫抑制环境。进一步的研究表明，IRE诱导细胞坏死，并引起与CD8+T细胞免疫相关的DAMPs的大量释放。另一方面，积极探索全身治疗对免疫微环境的影响作用，我们发现PD-L1表达上调与多西他赛(DTX)耐药发生相关。同时还发现活化ATM联合NEMO在DTX化疗中具有新的免疫抑制和促瘤功能。研究结果表明，ATM和NEMO功能抑制均可钝化肿瘤细胞中DTX诱导的PD-L1表达，从而揭示了一种通过PD-L1的上调而产生DTX耐药的新机制，可以开发以DTX和NEMO或ATM抑制剂的联合治疗的新型治疗策略，以克服与使用DTX相关的肿瘤免疫耐受。综上，本课题研究证明IRE能有效消融肿瘤，并阐明了IRE消融后免疫调控及免疫微环境变化的特点，为提高IRE的临床疗效及联合新疗法的开展提供理论基础，受局部治疗引起肿瘤免疫微环境改变的启示，更进一步发现一种潜在的免疫检查点抑制剂的替代治疗方法，有望为对免疫检查点抑制剂疗法无效的患者带来获益。

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