Miz1介导的线粒体自噬对肝癌免疫治疗反应性影响的机制研究

免疫治疗是肝癌最有希望的治疗手段，但总体反应率是治疗成败的关键。对肝癌PD1抗体治疗反应高低两组病人标本进行高通量测序，发现肝癌Miz1表达与免疫治疗反应密切相关。可能的机制是，Miz1下调导致线粒体自噬障碍，通过抑制MHC-I类分子导致免疫逃逸，同时增加IL-12分泌引起T细胞耗竭。本研究拟对接受肝癌免疫治疗的病人开展深入研究，结合Miz1和TOX等相关基因肝脏和T细胞特异性敲除小鼠，研究肝癌PD1免疫治疗反应性差异的机制，揭示Miz1通过调控线粒体自噬，影响MHC-I分子表达及IL-12分泌导致T细胞耗竭的原因，并针对机制研究获得的关键因子，利用PDX人肝癌和DEN+CCL4小鼠肝癌模型，使用T细胞修饰和过继输注、腹腔注射促进线粒体自噬剂，结合PD1治疗，观察其对小鼠肝癌的治疗作用。通过以上研究有望找出肝癌PD1治疗反应性低的原因，并通过联合治疗提高疗效，为临床肝癌综合治疗提供新方法。

Immunotherapy is the most promising treatment for advanced hepatocellular carcinoma (HCC). However, the Over Response Rate (ORR) is the critical issue in determining the effect of immunotherapy. Based on the high-throughput sequencing data for the different ORR of HCC patients undergoing anti-PD-1 therapy, we found that the expression of Miz1 in liver cancer is related to the immunotherapy ORR. The possible mechanism is that the down-regulation of Miz1 can lead to mitophagy failure in HCC cells, which induces immune escape by inhibiting the expression of MHC-I antigen, meanwhile induces T cell exhaustion by increasing interleukin-12 (IL-12). Therefore, this study proposed to analyze clinical samples obtained from the HCC patients undergoing immunotherapy, explore the mechanism of reduced HCC immunotherapy ORR induced by Miz1-related mitophagy failure, mitophagy failure-related MHC-I antigen switch and IL-12-related T cell exhaustion by using Miz1 and Tox tissue-specific knockout mice. Moreover, by targeting regulatory factors obtained from the study, the experimental intervention will be carried out including adoptive cell transfer and mitophagy activator combined with anti-PD-1 immunotherapy based on PDX- and DEN+CCL4-derived mice HCC model. This proposed project will clarify the potential causes of low ORR in HCC anti-PD-1 treatment and find a new approach of comprehensive treatment for HCC in the future.