肝癌相关成纤维细胞介导肝癌免疫逃逸的分子机制研究

The microenvironment of hepatocellular carcinoma（HCC）,especially the local status of immune response, shows the significant impact on tumor progression. However the underlying mechanisms are not fully understood. Hepatocellular carcinoma-associated fibroblasts（HCC-CAFs） is the major components in the microenvironment,and our previous study shows that HCC-CAFs can impair the function of NK cell via the secretion of the soluble molecules such as PGE2，and also promote the generation of the Th17 cell，Treg cell as well as tolerogenic dendritic cell. Therefore, we hypothesize that HCC-CAFs can induce the local immune tolerance by regulating the phenotype and function of these immune cells in HCC，and thereby create favorable conditions for tumor progression. In our present study, our group will thoroughly study the effect of HCC-CAFs on the phenotype and function of the NK cell，dendritic cell，macrophage , T cell and so on，and try to find the key factor and potential signal pathway through the established coculture model of HCC-CAFs and these immune cells in vitro. Furthermore, we will verify our findings using the clinical tissue samples. These results not only help us preferably understand the mechanism of the immune escape in HCC, but also provide the evidences for HCC molecular staging and new targeted anticancer strategy based on HCC-CAF.

肝癌局部免疫应答状态可显著影响肝癌的进展，肝癌相关成纤维细胞(HCC-CAFs)作为肝癌的重要间质细胞之一,其在肝癌免疫微环境中的作用尚待阐明。 我们课题组首次报道了HCC-CAFs可削弱NK细胞的免疫监控功能（Cancer Letters, 2012），进一步研究发现HCC-CAFs可诱导产生Th17，Treg以及免疫耐受表型的DC细胞产生，故我们推测HCC-CAFs可能通过调控局部免疫细胞表型和功能诱导"免疫耐受"，来营造利于肝癌免疫逃逸的微环境。为此，本课题拟通过HCC-CAFs和免疫细胞的体外共培养模型，以及临床样本验证，来系统地研究HCC-CAFs对NK细胞，DC细胞，肿瘤相关巨噬细胞等免疫细胞表型和功能的影响，阐明其中的关键因子及信号通路。所得的结果不仅有助于我们更好理解肝癌免疫逃逸的分子机制，更可为研制以HCC-CAFs为靶标的肿瘤分子分期标准和新型防治手段提供理论基础。

肝癌局部免疫应答状态可显著影响肝癌的进展，肝癌相关成纤维细胞(HCC-CAFs)作为肝癌的重要间质细胞之一,其在肝癌免疫微环境中的作用尚待阐明。本项目系统研究了HCC-CAFs对各种免疫细胞表型和功能影响，发现HCC-CAFs可以影响髓源性抑制细胞、树突状细胞和中性粒细胞等免疫细胞的表型和功能，HCC-CAFs可以将正常外周血免疫细胞诱导为肿瘤相关免疫细胞，这群细胞具有负性调控机体免疫系统，从而促进肝癌免疫逃逸的发生。在机制探究中，发现HCC-CAFs分泌的IL6和SDF1a起着关键作用，其中SDF1a主要参与了免疫细胞向肿瘤局部趋化作用，而IL6主要参与了免疫细胞向肿瘤相关免疫细胞转变过程，其主要通过激活JAK-STAT3信号通路促进免疫细胞表型和功能转变。本项目从不同层面剖析了HCC-CAFs促进肝癌免疫逃逸的过程及其相关机制，揭示了肝癌免疫逃逸的新机制，不仅有利于我们更全面的理解肝癌免疫逃逸的机理，也为研制以HCC-CAFs为靶标的肿瘤分子分期标准和新型防治手段提供理论基础。