共刺激分子HVEM调控肝癌细胞免疫逃逸的机制

Abnormal expression of costimulatory molecules in tumor microenvironment is one of mechanisms of immune escape of tumor. In our previous study, we found that down-regulation of HVEM in liver cancer tissues demonstrated a poor prognosis in the hepatocellular carcinoma (HCC) patients. Up-regulation HVEM expression in hepatoma cells could significantly enhance their killing sensitivity from NK cells. Therefore, we speculate that HVEM may play a important role in helping hepatoma cells escaping from immune surveillance. However, the underlying mechanism is still unknown. In this study, NK cells lead by hepatoma cells, which the HVEM expression has been up-regulated or interfered, will be observed. The effect of HVEM on the expression of immunosuppressive molecules in hepatoma cells will also been observed. Immunohistochemistry and immunofluorescence are employed to examine the correlation between the expression of HVEM in liver cancer tissue, NK cells cytotoxicity and the expression of immunosuppressive molecules in hepatoma cells in order to clarify the effect of HVEM on immunosuppressive state in HCC and their role in the development of HCC. This experiment improves the therapeutic effect of immunologic treatment based on HVEM as a target on hepatocellular carcinoma with evidence.

肝癌的发生发展与肝癌细胞免疫共刺激分子表达异常造成的免疫逃逸有关。前期研究发现肝癌组织中免疫共刺激分子HVEM(herpes virus entry mediator)表达降低多提示患者预后较差，上调HVEM在肝癌细胞中的表达可显著增强其对NK细胞杀伤的敏感性。推测肝癌细胞免疫逃逸可能与其HVEM表达缺失有关，但具体机制尚不明确。本课题拟通过在肝癌细胞中干扰或过表达HVEM后观察其对NK细胞亚群功能的影响，观察肝癌细胞免疫抑制分子表达变化。利用免疫组化及荧光染色，观察肝癌组织中HVEM的表达与局部NK细胞数量及肝癌细胞免疫抑制分子表达的关系，明确HVEM影响肝癌局部免疫抑制功能与肝癌发展转归的相关性，阐明HVEM调控的肝癌细胞免疫逃逸在肝癌发生发展中的作用及其机制，为肝癌临床治疗寻找新的靶点提供理论基础和实验依据。

肝癌的发生发展与肝癌细胞免疫共刺激分子表达异常造成的免疫逃逸有关。前期研究发现肝癌组织中免疫共刺激分子HVEM(herpes virus entry mediator)表达降低多提示患者预后较差，上调HVEM在肝癌细胞中的表达可显著增强其对NK细胞杀伤的敏感性。推测肝癌细胞免疫逃逸可能与其HVEM表达缺失有关，但具体机制尚不明确。本课题拟通过在肝癌细胞中干扰或过表达HVEM后观察其对T细胞及NK细胞亚群功能的影响，观察肝癌细胞免疫抑制分子表达变化。利用免疫组化及荧光染色，观察肝癌组织中HVEM的表达与局部CD69+/CD8+T细胞、NK细胞数量和活化相关分子表达及肝癌细胞免疫抑制分子表达的关系，明确HVEM影响肝癌局部免疫抑制功能与肝癌发展转归的相关性，阐明HVEM调控的肝癌细胞免疫逃逸在肝癌发生发展中的作用及其机制。我们已完成有关研究内容，相关结果已整理论文，目前正在投稿过程中。在进一步扩展研究中我们还发现HVEM与肝癌细胞化疗抵抗有关，上调肝癌细胞中HVEM表达可有效提高化疗敏感性。我们还发现炎症微环境中的间充质干细胞通过诱导自噬促进肝癌细胞的化疗抵抗。此外，SIRT1是sirtuin家族家族成员，能够将组蛋白去乙酰化，我们发现SIRT1通过诱导肝癌细胞发生上皮间质转化促进肝癌细胞侵袭转移，肝癌组织中SIRT1的表达与肝癌患者预后呈现负相关。本项目为以HVEM 和SIRT1为靶标，提高肝癌免疫治疗的效果、提高化疗敏感性提供基础。