CD317负调控肝脏免疫应答促进肝细胞肝癌发生发展的作用机制研究

Hepatocellular carcinoma (HCC) is one of the most common cancers with high mortality due to limited diagnostic and therapeutic options. Identification of prognostic markers and development of novel therapeutic approaches are critically important. CD317 is upregulated in HCC with unclear function. As reported, CD317 is a novel ligand for an immune receptor called immunoglobulin-like transcript 7 (ILT7) and plays a key role in the regulation of plasmacytoid dendritic cells (pDCs) activation. Recombinant CD317-ECD (extracellular domain) can suppress airway inflammation in mouse models of mild chronic asthma and allergen-induced acute exacerbation of asthma. Otherwise, we also found that recombinant CD317-ECD can interact with unclear receptors expressed in NK cells and T cells. CD317 directly inhibits the cytolyticactivity of NK cells in vitro. Accordingly, we speculate that CD317 may serve as an exogenous immune inhibitory protein that may be involved in tumor immune escape. However, there is no literature reported regarding whether and how CD317 participated in tumor immune escape. Hence, in this study, we plan to elucidate the role and mechanism of tumor-derived CD317 in the regulation of liver immune response during HCC development, which may provide new information for HCC diagnosis and therapy.

肝细胞肝癌（Hepatocellular carcinoma, HCC）是一类诊疗困难、死亡率高的恶性肿瘤。急需新靶点、新方法来提高临床治疗水平。CD317在HCC中表达上调，但对疾病发展尤其是肿瘤免疫逃逸的作用尚不清楚。研究发现，CD317通过ILT7受体抑制类浆树突状细胞（Plasmacytoid dendritic cells，pDCs）活化，CD317胞外段蛋白具有抗炎、抑制哮喘的功能。我们也发现，CD317胞外段蛋白能结合于NK细胞、T细胞表面，而靶细胞表面CD317具有抑制NK细胞体外杀伤功能的作用，提示CD317是一个外源性免疫抑制蛋白，可能促进肿瘤免疫逃逸。但截至目前尚没有这方面的报道。因此，本项目拟以肿瘤免疫为关注点，探讨肝癌细胞CD317通过抑制肝脏免疫应答促进HCC发生发展的作用及其分子机制，为HCC诊疗手段开发提供新的思路。

肝细胞肝癌（HCC）是一种严重威胁人类生命健康的恶性肿瘤，进展快、病程短，诊疗困难。迄今为止，尚没有太好的治疗办法，5年生存率极低（~12%）。我国肝细胞肝癌患者众多，约占全球的55%，造成的经济和社会负担重。因此，探讨肝细胞肝癌发病机制，寻找新的治疗靶点、开发更有效的治疗手段依然是目前研究的热点、重点。CD317在肝细胞肝癌的表达水平远高于正常肝组织，但其是否参与肝癌发病过程此前并不清楚。本研究分别从癌细胞增殖调控和免疫逃逸两个角度探讨了CD317在HCC发生发展过程中的作用机制，发现CD317不仅可以通过脂筏依赖的方式增强EGFR活化，促进肝癌细胞增殖；还通过RICH2介导细胞骨架调控、维持细胞膜功能，帮助癌细胞抵抗NK或CAR-NK介导的免疫杀伤，促进肿瘤免疫逃逸。研究成果不仅证实了CD317的促肿瘤功能，而且阐明了新的EGFR调控、肿瘤免疫逃逸机制，为肝细胞肝癌治疗策略开发提供了新的靶点和理论指导，兼具理论意义和应用潜力。