CD147相关的糖代谢重编程诱导的肝癌免疫抑制及相关机制研究

Mechanisms underlying immunosuppression induced in hepatocellular carcinoma (HCC) is widely investigated, but the role of reprogramming of glucose metabolism in it is not clear. We previously identified a FOXP3+CD3+CD56+ population with immunosuppressive function in cancer tissues of HCC, and transforming growth factor β1 (TGF-β1) could effectively induce FOXP3 expression in natural T (CD3+CD56+) cells in vitro. As a HCC associated antigen, CD147 plays an important role in tumorigenesis and progression through multiple mechanisms, including reprogramming of glucose metabolism. In this study, we aim to explore the correlation between immunosuppression induced in cancer tissues of HCC and the reprogramming of glucose metabolism via flow cytometric study to tumor infiltrating lymphocytes (TIL) and immunohistochemical assays to tissue specimens. Immunosuppression and associated mechanism induced by CD147-mediated glucose metabolic reprogramming in hepatocellular carcinoma is under investigation through establishment of different HCC cell lines with various level of CD147 expression and co-culture with natural T cells, and detection of induced expression of FOXP3 by addition of TGF-β1 combined with acidic stimulation in vitro. This study is designed to reveal an innovative mechanism involving reprogramming of glucose metabolism responsible for immunosuppression induced in HCC, thus providing a theoretical basis for tumor immunotherapy combined with glucose metabolism-targeting intervention treatment.

肝癌免疫抑制的诱导机制研究较多，但是糖代谢重编程相关的诱导机制研究较少。我们前期研究工作在肝癌组织局部首次发现了具有免疫抑制功能的FOXP3+natural T细胞，并且TGF-β1能够体外诱导natural T细胞表达FOXP3。CD147作为一种肝癌相关抗原，通过糖代谢重编程等多种机制参与肝癌的发生和发展。在本研究中，我们拟通过TIL流式染色和癌组织免疫组织化学染色，对于肝癌组织局部淋巴细胞免疫抑制状态与肝癌细胞糖代谢重编程之间的相关性进行研究；通过不同CD147表达水平肝癌细胞株的构建及其与natural T细胞的共同培养实验、TGF-β1联合酸性刺激诱导natural T细胞表达FOXP3的体外细胞实验，对于CD147相关的糖代谢重编程引发的肝癌免疫抑制及相关机制进行研究。本研究旨在揭示诱导肝癌免疫抑制的糖代谢重编程相关诱导机制，为肝癌免疫治疗联合糖代谢干预治疗提供理论基础。

从代谢的角度来看，癌症可以被认为是以重编程的糖酵解代谢为特征的代谢性疾病。本研究的目的是研究肝细胞癌（HCC）中CD147分子介导的葡萄糖代谢调控及其对肿瘤微环境中免疫应答改变的影响。通过建立几种CD147表达水平不同的HCC细胞系和相应的裸鼠异种移植物，用于直接研究CD147在葡萄糖代谢重编程中的作用及可能的分子机制；通过免疫组织化学（IHC）分析和流式细胞分析方法来研究肝癌中重编程糖酵解与免疫抑制之间的关系。研究结果发现CD147表达上调与肝癌组织中GLUT1，MCT1分子的表达增强正相关；CD147可以通过PI3K / Akt / mTOR信号通路在体外促进HCC细胞系的糖酵解代谢；肝癌组织中免疫抑制性淋巴细胞浸润与CD147表达之间存在正相关，并且在体外用乳酸刺激可以诱导产生FOXP3表达阳性的调节性T细胞。总之，CD147通过PI3K / Akt / mTOR信号通路促进肝癌的糖酵解代谢，并导致了肝癌局部的免疫抑制。