肝细胞癌发生及进展中免疫微环境单细胞水平多组分的时空分析

Hepatocellular carcinoma is the third most common malignant tumor in China, and the prognosis is very poor. However, the current effective treatment for hepatocellular carcinoma is extremely limited, and it is urgent to develop new effective treatment methods. The tumor microenvironment is crucial for the development of tumors, and comprehensive and systematic understanding of the immune microenvironment can help to discover new tumor therapeutic targets. To this end, we will systematically study the role of the immune microenvironment in hepatocellular carcinoma at the single cell level. Specifically, we will depict the dynamic traits of immune microenvironment cell subsets and regulatory networks during the development of Hepatocellular carcinoma in the mouse model. In addition, the effects of certain immune cell on the microenvironmental map of Hepatocellular carcinoma will be studied, to analyze the interaction between different components of the tumor microenvironment and deepen our understanding to the immune spectrum and molecular state of tumor microenvironment. Finally, we will verify the key immune cells or molecules found in clinical samples of hepatocellular carcinoma and explore their possible impact on disease progression and treatment response, to reveal new cancer immunotherapy and discover new targets to help diagnose and treat hepatocellular carcinoma.

肝癌是我国发病率第三的恶性肿瘤，预后非常差，而当前针对肝癌的有效治疗手段极为有限，亟需开发新的有效的治疗方法。而肿瘤微环境对肿瘤发生发展至关重要，全面系统地认识免疫微环境有助于发现新的肿瘤治疗靶点。为此，我们将在单细胞水平上系统地研究免疫微环境在肝细胞癌中的作用。具体将在肝癌小鼠模型中，动态描绘肝癌进展过程中免疫微环境细胞亚群的性状、免疫细胞和分子调控网络。并且，还将在肝癌小鼠模型中，研究各免疫细胞组分对肝癌微环境图谱的影响，了解肿瘤微环境不同组分间的相互作用，综合分析免疫谱和分子状态，加深对肿瘤微环境免疫细胞行为的理解。最后，我们将发现的关键免疫细胞或分子，在肝癌临床样本上验证并探讨其对疾病进展和治疗应答的可能影响，助力于新的肿瘤免疫疗法和新靶点的发现，帮助肝癌的诊断和治疗。

本项目1)在单细胞水平上描绘了小鼠肝癌发生发展过程中肿瘤区域微环境内免疫图谱的变化，阐明了多种免疫细胞组分对肝癌的影响；2)确定了在小鼠肝癌模型中肿瘤相关性巨噬细胞对肝癌的发生发展具有重要影响；一群特定高脂质代谢状态的肿瘤相关性巨噬细胞具有更强的免疫抑制功能，阐明了FABP5在其中发挥关键作用；3)筛选并鉴定了多种影响肝癌进展的circRNA，验证了其对肝癌表型、功能和糖酵解能力的异常影响，明确了其内在的通路机制；4)对临床标本进行测序分析，阐明了影响早期肝癌发生进展的微环境因素；鉴定了肝癌新抗原和公共抗原AFP候选肽段，筛选了相关特异性TCR序列并进行了免疫学功能验证。