肝星状细胞分泌C3诱导Mo-MDSC扩增和功能促进肝癌生长的研究

Liver is an "immune amnesty" organ, the activated hepatic stellate cells (HSC) have a powerful immune regulating function which can induce myeloid-derived suppressor cell (MDSC) accumulation. But its mechanism is unclear. HSC promoted the accumulation of G-MDSC, one of the MDSC subgroup by PGE2/EP4 pathway. However, the mechanism of HSC promoted Mo-MDSC, another subset of MDSC, in the liver cancer microenvironment is not clear. To explore this issue, we found that the ability of HSC to induce MDSC and Mo-MDSC accumulation and function was impaired after down-regulated the complement component 3(C3) level of HSC. In this project, we try to knockdown or up-regulated the C3 level of HSC to further elucidate the mechanism of HSC induced Mo-MDSC accumulation and function; and the mechanism of HSC promoted the growth of liver cancer would be discussed. This project would be the first time to elucidate the molecular mechanism of HSC inducing Mo-MDSC accumulation and function to promote liver cancer growth. This project would also provide a new theoretical for the mechanism of HSC promoted liver cancer growth, and an experimental evidence for the immunotherapy of liver cancer and other cancers.

肝脏是一个具有“免疫特赦”的脏器，肝癌微环境中活化的肝星状细胞（HSC）具有强大的免疫调节功能，能诱导免疫抑制细胞——髓系来源抑制性细胞（MDSC）扩增，但其机制尚不清楚。活化的HSC通过PGE2/EP4通路促进MDSC亚群中的G-MDSC的扩增，促进肝癌的生长。然而HSC对MDSC另一个亚群Mo-MDSC的调控机制尚不清楚。为了探索HSC诱导Mo-MDSC扩增，促进肝癌生长的机制，我们发现HSC能够增强MDSC的功能，敲低HSC的补体C3水平后，其诱导MDSC及Mo-MDSC的能力降低。本课题拟进一步通过干扰及过表达HSC的C3的水平，从MDSC扩增和功能方面着手，探讨HSC诱导Mo-MDSC扩增和功能促进肝癌生长的机制。本项目研究成果将首次阐明HSC促Mo-MDSC扩增和功能的机制，从全新的解度阐明HSC促进肝癌生长的机制，为肝癌及其他癌症的发生机制和免疫治疗研究提供理论和实验依据。

原发性肝癌是全球第五大常见的恶性肿瘤，肝癌微环境中活化的肝星状细胞（HSCs）具有强大的免疫调节功能，我们研究发现，HSCs能够通过分泌补体C3抑制骨髓细胞成熟，并诱导骨髓来源抑制性细胞MDSCs及其亚群（G-MDSCs和Mo-MDSCs）的扩增。敲低HSCs的C3表达，HSCs对MDSCs的扩增明显受到抑制，且HSCs对T细胞增殖的抑制也减弱。体内实验也证实了HSCs敲低C3后，其对肝癌的促进作用减弱。表面HSCs通过分泌C3促进MDSCs的扩增进而促进肝癌的发展。同时，我们还发现HSC-条件培养基（HSC-CM）诱导的骨髓来源的细胞与脾细胞的迁移，特别是MDSCs迁移。使用趋化因子中和抗体和趋化因子受体抑制剂，我们发现，HSCs通过SDF-1 / CXCR4轴促进MDSCs迁移。原位小鼠肝癌模型表明与CXCR4抑制剂预处理的MDSCs或注射的该SDF-1-敲低的HSCs能显著抑制MDSCs迁移至荷瘤小鼠的脾脏和肝脏。表明HSCs通过SDF-1 / CXCR4轴介导MDSCs迁移,这为靶向HSCs调节肝癌环境提供一种潜在有效的方法。另外，我们发现HBXIP表达水平与HCC有重要的临床意义。我们发现HBXIP肝癌组织中明显上调，并与血管浸润，肿瘤转移和肝癌患者的不良预后相关。 HBXIP促进体外细胞迁移和侵袭，促进HCC在体内的转移。而HBXIP的这种作用可能是通过c-myc上调MMP15的表达相关。HBXIP-MMP15促进肝癌的转移，可能成为肝癌预后的指标及肝癌转移的治疗靶点。