肝癌中唾液酸化IgG抗体的形成机制及其功能研究

B cell plays an important role in the progression of human cancers. However, its regulation, maturation and functions in tumors are still unclear. We previous found that in human hepatocellular carcinoma (HCC), CXCR3 positive B cells were selectively recruited into tumor and differentiated into IgG-producing plasma cells in situ (Gastroenterology 2019). We have recently observed that IgG antibodies in HCC tissues were highly sialylated. Meanwhile, we observed that macrophages in HCC tumors significantly expressed type II Fc receptor DC-SIGN, which bound to sialylated antibodies. More importantly, the density of DC-SIGN positive macrophages in tumors was negatively correlated with the clinical outcome of patients. It indicated that sialylated IgG antibodies may induce protumorigenic macrophages by acting on DC-SIGN. With the combination of clinical sample examination and ex vivo/in vivo study, we will systematically investigate the mechanism of formation of sialylated IgG antibodies in hepatocellular carcinoma. Thereafter, we will analyze the effect of sialylated IgG antibodies on the functions of DC-SIGN positive macrophages, and demonstrate the key factors and underlying mechanism. The results will clarify the role of sialylated IgG antibodies in the progression of hepatocellular carcinoma, and provide theoretical basis for the development of molecular staging criteria and prevention methods targeting sialylated IgG antibodies.

B细胞在人肿瘤进展中起重要的作用，但其分化及功能调控仍未清楚。我们前期发现人肝癌微环境选择性募集CXCR3阳性B细胞，并促使其分化成产生IgG的浆细胞。我们新近观察到：这些肝癌组织来源的IgG抗体选择性发生唾液酸化修饰；与此同时，肝癌中巨噬细胞显著高表达可结合唾液酸化抗体的II型Fc受体DC-SIGN，且其数量越多，患者术后生存时间越短。由此推测，唾液酸化IgG抗体很可能通过作用于DC-SIGN来改变巨噬细胞的极化，进而影响肿瘤的进展。以此为基础，本项目拟结合临床样本分析和实验模型，来系统的研究肝癌中唾液酸化IgG抗体产生的机制，分析其对DC-SIGN阳性巨噬细胞表型/功能、对肿瘤进展/退化的影响，阐明其中的关键因素及潜在调控网络。所得结果将明确唾液酸化IgG抗体在肝癌进展中的作用，为研制以唾液酸化IgG抗体及其调控网络为靶标的肿瘤分子分期标准和防治手段提供理论基础。

B细胞是肿瘤间质的重要组分，但其功能调控及对肿瘤治疗的影响目前仍未清楚。使用质谱分析，我们发现肿瘤中B细胞来源的IgG抗体Fc区发生唾液酸化修饰。更重要的是，免疫检查点阻断（ICB）治疗进一步催化IgG唾液酸化的上调。进一步研究发现，效应T细胞通过干扰素（IFN）-g-ST6Gal-I依赖的途径触发IgG的唾液酸化。这些唾液酸化IgG抗体进一步作用于DC-SIGN+巨噬细胞，刺激巨噬细胞胞内Raf-1介导的ATF3升高，使cGAS-STING通路失活从而使巨噬细胞丢失产生I型IFN的能力。尽管肿瘤中IgG唾液酸化的增强提示良好的免疫治疗疗效，但阻断IgG唾液酸化进一步增强ICB治疗后的抗肿瘤T细胞免疫。这些结果不仅有助于我们更好的理解肿瘤中B细胞及抗体的功能及其调控肿瘤进展的机制，更可为研制以调控B细胞及抗体特征为靶标的新型肿瘤防治手段奠定理论基础。