化疗栓塞联合PD-1免疫检查点阻断剂疗法治疗肝癌的疗效与机制研究

Chemoembolization of hepatocellular carcinoma induces substantial tumor cell death through intraarterial delivery of chemotherapeutic agents and blockage of the tumor-feeding vessels, but its effect on tumor immunity remains unclear. Studies show that hepatocellular carcinoma escapes from immunosurveillance by special mechanism, in which the immune checkpoint programmed cell death protein 1 (PD-1) and its ligand PD-L1 play an important role. PD-1/PD-L1 pathway blockade is currently the leading immunotherapy for cancer, and combining the immunomodulation with conventional therapies possesses synergistic anti-tumor effects. Our previous studies have found that hypoxia-inducible factor 1α was highly expressed in the residual tumor after chemoembolization, which may be involved in immune escape by directly upregulating PD-L1 expression of tumor cells. Therefore, this study intents to use PD-1 monoclonal antibody as PD-1 pathway blocker, and conduct experiments to investigate 1) the effect of chemoembolization on PD-1 pathway and its relative tumor immunity, 2) the expression of PD-1 ligands in liver cancer cells under chemotherapy and hypoxic conditions, and the effects of PD-1 blocker on the PD-1 ligands expression, and 3) the therapeutic efficacy of chemoembolization combined with PD-1 blocker and the potential mechanism of action of the combination treatment for liver cancer. This study will advance the research of transcatheter therapies for liver cancer into the field of tumor immunity, thus contributing to the development of a novel therapeutic strategy for improving the therapeutic effectiveness.

肝癌化疗栓塞通过动脉内灌注化疗药和阻断肿瘤血供诱导大量肿瘤细胞死亡，但它对肿瘤免疫的影响尚不明确。研究发现肝癌表现为免疫逃逸，而免疫检查点程序性细胞死亡蛋白1(PD-1)及其配体PD-L1在其中起重要作用。PD-1/PD-L1阻断剂疗法是目前肿瘤免疫治疗的主导疗法，并与其他常规疗法具有协同效应。我们前期研究发现肝癌TACE术后残存肿瘤缺氧诱导因子1α高表达，而后者可能通过直接上调肿瘤细胞PD-L1表达参与免疫逃逸。因此，本项目拟采用PD-1单抗作为PD-1免疫检查点阻断剂，通过动物和细胞实验研究化疗栓塞对肝癌PD-1通路及相关肿瘤免疫的影响，研究化疗和缺氧状态下肝癌细胞PD-1配体的表达以及PD-1阻断剂对其表达的影响，研究化疗栓塞联合PD-1阻断剂治疗肝癌的疗效，并探索联合治疗机制。本项目将肝癌介入治疗研究深入到肿瘤免疫学领域，有望为肝癌经导管介入治疗提供新的治疗策略。

经动脉化疗栓塞(TACE)是治疗肝癌的有效方法，但TACE对肿瘤免疫状态的影响，以及TACE联合免疫治疗的疗效及机制尚不明确。本项目采用程序性细胞死亡蛋白1(PD-1)单抗作为免疫检查点阻断剂，通过动物和细胞实验研究(1)化疗栓塞对肝癌PD-1通路及相关肿瘤免疫状态的影响; (2)研究化疗和缺氧状态下肝癌细胞PD-1 配体的表达; (3)研究化疗栓塞联合PD-1单抗治疗肝癌的疗效，探索联合治疗机制。本研究发现(1)TACE处理导致大鼠肝癌肿瘤组织HIF-1、PD-L1表达增加，肿瘤内浸润淋巴细胞CD45+、CD8+、CD4+数量显著性增加，CD8+、CD4+T细胞表达PD-1，肿瘤基因表达谱发生变化，有助于形成有利于PD-1阻断剂疗效的免疫支撑肿瘤微环境；(2)缺氧状态及阿霉素处理可诱导HepG2肿瘤细胞PD-L1表达；(3)TACE联合PD-1单抗处理可提高大鼠肝癌的肿瘤反应、降低肝内肿瘤负荷及肝外转移、延长动物生存时间，其肿瘤基因表达谱显示与T细胞活性相关基因表达谱增加，提示抗肿瘤免疫应答增强。本项目研究结果可能为TACE联合PD-1抗体治疗肝癌提供了实验依据，有助于提高肝癌综合治疗效果。