射频消融术后IL-33介导肿瘤免疫抑制的调控机制及干预策略研究

Radiofrequency ablation (RFA) is a widely used minimally invasive treatment for solid tumors in clinic. In a previous study, we demonstrated that RFA enhanced T cell-mediated antitumor immune response in a distant tumor. However, adaptive immunosuppression in tumor microenvironment limited the antitumor immune effects of RFA. In the present study, we focused on the mechanism and intervention strategy of adaptive immunosuppression after RFA. In preliminary experiments, we found that the expression of interleukin-33 (IL-33) was largely increased in distant tumor cells after RFA treatment. IL-33 receptor ST2 was highly expressed on regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), but less on effector T cells. Based on these findings, we will study and elucidate the role of RFA and interferon -γ (IFN-γ) in inducing IL-33/ST2 expression in a distant tumor and its clinical significance. We will also intent to reveal that tumor cells stimulate immunosuppressive cells by releasing IL-33, and then inhibit RFA-elicited antitumor immunity as a negative feedback mechanism. Further, we will explore the antitumor immune effect of RFA combined with anti-ST2 mAb. This study is aim to provide a novel strategy to optimize the use of RFA and blockade of IL-33/ST2 signal pathway in combined immunotherapy for cancer.

射频消融（RFA）是临床应用广泛的肿瘤微创治疗方法。我们已有的研究发现RFA可增强远处肿瘤中T细胞的杀伤效应，但肿瘤微环境中适应性免疫抑制的发生限制了RFA的抗肿瘤免疫功能。本项目聚焦的科学问题是RFA后适应性免疫抑制发生的调控机制及干预策略。我们的预初实验发现，RFA术后肿瘤细胞的白介素33（IL-33）表达上调；IL-33受体ST2主要在抑制免疫反应的调节性T细胞与MDSC高表达，而极少表达于杀伤效应T细胞。鉴此，本项目拟研究和明晰RFA及炎症因子IFN-γ对远处肿瘤中IL-33和ST2表达的作用与临床意义；揭示肿瘤细胞通过释放IL-33刺激免疫抑制细胞，负反馈抑制抗肿瘤免疫反应的机制；明确RFA联合ST2单抗应用对抗肿瘤免疫反应的调节作用；建立靶向干预IL-33/ST2信号优化RFA治疗的联合免疫干预新策略。

射频消融（RFA）是一种应用广泛的肿瘤微创治疗方法。研究表明RFA能激活肿瘤抗原特异性T细胞免疫应答。本项目聚焦消融远处肿瘤与局部残余肿瘤免疫微环境的特征与调控机制，探讨消融联合免疫治疗的新策略。.一．I IL-33/ST2信号对RFA术后抗肿瘤免疫反应的调节作用.我们通过分析病例分析与小鼠模型，证实RFA消融增强消融区外肿瘤内T细胞反应，同时上调IL-33表达，而IL-33的受体ST2主要在Treg中表达，而且ST2的表达与CD4+T细胞与Treg表型与免疫抑制功能相关。利用基因敲除，阻断ST2信号可增强消融区外肿瘤T细胞抗肿瘤免疫反应，并增强RFA对对远处肿瘤的抑制作用。该研究结果靶向干预IL-33/ST2信号联合RFA治疗恶性肿瘤提供了试验依据。.二．不完全消融促进肿瘤快速进展并导致PD-1免疫治疗抵抗.射频消融术（RFA）可增强肿瘤抗原特异性T细胞反应，增强免疫治疗的效果。通过病例对照研究我们发现由于不完全RFA（iRFA）导致的残余与结直肠癌肝转移（CRCLM）患者的早期新转移的发生以及总生存时间的缩短相关。利用小鼠模型，我们证明了iRFA促进肿瘤进展并抑制抗PD-1治疗的疗效。免疫分析显示，iRFA在局部残余肿瘤激发持续存在的炎症反应，该炎症由髓源性细胞介导。残余中浸润的髓源性细胞可抑制肿瘤中的T细胞抗肿瘤活性，介导免疫抑制形成。机制上，残余肿瘤中单核细胞和肿瘤相关巨噬细胞（TAM）的招募聚集与肿瘤细胞来源的CCL2有关。TAM通过分泌TNFα促进肿瘤细胞产生CCL2。因此，残余肿瘤细胞通过与TAM的交互作用，形成正反馈调节机制，促进局部慢性炎症形成。另外，我们证实CCR2拮抗剂治疗可部分逆转残余肿瘤对PD-1治疗的耐药，为iRFA后残余肿瘤的发生提供了挽救性治疗方案。