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

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.

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。

本研究《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》（No. 81771956）旨在探究JAK2抑制剂序贯RFA联合PD-1单抗治疗HCC的机制及临床意义，拟通过JAK2阻断逆转PD-1单抗耐药现象以增强RFA治疗后的免疫效应，更好地激活抗肿瘤免疫并恢复失能 T 细胞。在本研究中，我们明确了由于RFA等治疗导致的免疫激活引起IFNg上调从而诱发出现的免疫抑制因素PD-L1与IDO等对肝癌临床治疗的预后影响以及具体调节机制，同时明确了肝癌免疫微环境中存在的其他免疫抑制因素VEGFA等对PD-1单抗治疗的负性调节作用以及药物靶向策略。不仅如此，我们还探究了多靶点酪氨酸激酶抑制剂仑伐替尼联合PD-1单抗在肝癌微环境中的协同机制以及可能存在的耐受因素。总的来说，我们基于介入治疗的免疫激活效应与引起PD-1单抗耐药的多重机制进行了广泛而深入的基础探究，并且本研究与临床治疗密切结合，为PD-1单抗的治疗使用以及其与肝癌中靶向药物的结合提供了理论依据，为临床医生的肝癌综合治疗方案提供了更多的选择。