JAK2通路在RFA联合免疫检查点阻断剂治疗肝癌耐药机制中的研究

射频消融（RFA）既能原位灭活瘤灶，又能激发机体免疫反应。然而，临床上RFA治疗肝癌后局部复发及远处转移率仍较高，提示RFA所激发的抗肿瘤免疫反应不足，无法有效控制局部残留和远处转移。已报道的研究及我们的前期结果均表明PD-1/PD-L1等免疫检查点抑制了免疫反应；近期数据也发现PD-1单抗联合RFA比单用的治疗效果要高，但仍然有约60%的患者无反应，提示还存在其他的免疫抑制机制。T细胞激活时分泌的IFN-γ会通过IFNGR-JAK通路上调PD-L1的表达。我们发现这条通路中的JAK2不仅提高PD-L1在肝癌细胞中的表达，还上调其他免疫检查点的表达，导致PD-1抗体治疗产生适应性耐药。因此我们认为在PD-1单抗与RFA的协同治疗中加入JAK2抑制剂能减轻免疫抑制，提高疗效。本项目将系统评估RFA联合PD-1单抗序贯JAK2抑制剂治疗肝癌的效果，建立高效的联合治疗方法，并深入研究其机制。

Radiofrequency ablation (RFA) is a useful therapy and has been widely appling in the treatment of hepatocellular carcinoma (HCC). Studies have showed that RFA can both induce coagulating necrosis and triger anti-tumor immunity. However, the local recurrence and distance metastases still happen at a high rate, which suggests that RFA induced immunity is not enough to control HCC. Our preliminary data and other’s results have showed that PD-1/PD-L1 and other immune checkpoints suppressed RFA-induced immune response. Combination of RFA and PD-1 antibody therapy increased objective response rate compared PD-1 antibody or RFA alone. However, it is much lower than expected, which suggested that other suppressive mechanisms. We and others found that T cell secreted IFN-γ during activation not only upregulated PD-L1 but also othe checkpoints on HCC via the IFNGR-JAK signaling pathway, which resulted in adaptive resistance during PD-1 antibody treatment. We further found that JAK2 is the key molecule for the expression of PD-L1 and other immune checkpoints in HCC. Therefore, we hypothesize that sequential JAK2 inhibitor applied after the combination of RFA and PD-1 blockade would maximize the anti-tumor immune response, thus improving the effect of treatment. In this study, we will explore the mechanism of JAK2-mediated PD-1 blockade resistance and evaluate the feasibility and efficacy of JAK2 inhibitor in sequential administration with RFA combined with PD-1 blockade. It will provide a theoretical basis for further clinical application.