以肿瘤相关巨噬细胞为靶点的α干扰素抗肝癌作用机制研究

Based on the high metastatic human hepatocellular carcinoma (HCC) nude mice model eatablished by our institute, we initially found that interferon alpha (IFNα) could inhibit the growth and metastasis of HCC. Then it was validated by clinical random trial performed by our institute. However, the total effects of IFNα could not completely meet the clinical needs in China. Therefore, it is urgent to find the mechanism and target of IFNα therapy. In our previous studies, we suggested that tumor associated macrophages (TAMs) was the target of IFNα in HCC, given the specific marker CD206 was found to identify TAMs in HCC tissues. Furthermore, it was found that HSP27 derived from macrophages was the key factor to mediate the effects of IFNα. This was a novel finding of the mechanism of IFNα therapy in cancer. This study will establish in vivo and in vitro mode of human HCC immune microenvironment in order to investigate the HSP27 related key molecule pathway involved in the impacts of IFNα on macrophage subsets transformation. In addition, we will validate the functions of above key molecules by gene transfection and small RNA interference and establish preliminary molecular model to predict the outcome of IFNα therapy in patients with HCC. Our study will help screen IFNα sensitive subpopulation and improve the outcomes of IFNα in HCC.

利用本所建立的肝癌高转移动物模型，我们在国际上首次发现α干扰素可以抑制肝癌的生长和转移，其疗效亦在临床随机对照试验中得到验证。然而，由于缺乏筛选治疗敏感人群的特异性标志，α干扰素对肝癌患者的总体疗效仍不能满足临床需求。寻找α干扰素的确切作用机制及靶点成为迫切需求。前期工作中，我们在发现肝癌组织中肿瘤相关巨噬细胞（TAMs）特异性标志物CD206的基础上，率先揭示TAMs是α干扰素治疗肝癌的作用靶点， 并利用高通量检测手段发现了TAMs参与α干扰素治疗的关键基因HSP27。迄今，国内外未见报道。在此基础上，本课题将模拟人体肝癌免疫微环境建立体内和体外模型，利用生物芯片和原代细胞分选等技术探讨TAMs中HSP27参与α干扰素抗肝癌机制的关键分子，并利用基因转染及RNA干扰技术对发现的关键分子进行功能验证，初步建立预测α干扰素疗效的分子模型，为筛选敏感个体和提高α干扰素临床疗效提供实验依据。

本项目组在前期工作基础上，建立模拟人体肝癌免疫微环境的体内和体外模型，利用生物芯片和原代细胞分选等技术筛选TAMs中HSP27参与α干扰素抗肝癌机制的IL-6、MAGL、DPYD等关键分子，并利用基因转染及RNA干扰技术对发现的关键分子进行功能验证，初步建立了预测α干扰素疗效的分子模型，为筛选敏感个体和提高α干扰素临床疗效提供了实验依据。本课题研究从临床实际问题出发，以提高α干扰素治疗肝癌效果为目标，以全新的视角从肿瘤免疫微环境为切入点探索α干扰素治疗肝癌新机制，证实HSP27在α干扰素调控巨噬细胞亚型中的作用并寻找相关分子通路，发现α干扰素干预靶点和筛选敏感人群的分子标志。通过上述研究，对α干扰素的作用机制做出了创新性发现，拓展了α干扰素对肿瘤免疫微环境作用方面的分子机制。为临床选择抗肝癌药物，包括与α干扰素协同免疫调节作用的药物提供依据，进一步提高了肝癌患者疗效。