肝癌中IL-21阳性细胞与B细胞功能性相互作用机制的研究

B cells constitute important components of the leukocytes infiltrating into the solid tumor stroma. The differentiation, maturation and activation of these B cells are closely regulated by the surrounding tissue microenvironments of the stroma. Recent studies indicated that IL-21, a kind of inflammatory cytokine, plays an important role in regulating B cells' activation, proliferation and functions. However, the underlying exact mechanisms concerning the functional interactions between IL-21 and B cells are not yet clear. Also, the source of IL-21 in the solid tumor stroma is still to be investigated. Most recently, we found that IL-21+ cells were enriched predominantly in the invading peritumoral stroma of hepatocellular carcinoma (HCC), and their densities were well correlated with those of B cells in the same invasion region. Simultaneously, we observed that high densities of the B cells infiltrating into the invading peritumoral stroma of HCC contributed to the tumorous angiogenesis (increased micro-vessel density) in the exact same area. Furthermore, high infiltration of peritumoral B cells was found to be positively correlated with poor survival of HCC patients and the disease progression... Based on the above observations, we create a project proposal which will systematically investigate the functional interactions between IL-21+ cells and B cells in human HCC tissue environments and try to figure out how these "cross talks" promote HCC progression or regression. The phenotypes and the various potential functions of the IL21+ cells and B cells will be evaluated in HCC tissue samples as well as in vitro/in vivo studies. The relevant in vitro findings will be examined in paired tumor and pre-tumor (chronic hepatitis or liver cirrhosis) tissue samples. Some clinical indexes, such as tumor angiogenesis, tumor staging and prognosis, will be integrated with the immunology study, and the potential relationship and relevance will be investigated. We believe that this project will give new insight into the fine-tuned collaborative interactions among different immune cells in tumor microenvironments and cancer immunoediting. With the accomplishment of this project and the clarification of the mechanisms, functional activities of IL-21+ cells and B cells might be modulated selectively and/or accordingly, which will subsequently provide a potential novel strategy for anticancer therapy.

B细胞是肿瘤间质的重要组分，其分化、成熟以及激活均受组织微环境的紧密调控。近年研究表明：IL-21对B细胞的活化、增殖及抗体分泌均起重要作用，但实体瘤中IL-21的来源及其与B细胞功能性相互作用的机制尚未清楚。我们新近发现：肝癌中IL-21+细胞富集于肿瘤侵袭边缘间质区域，其密度与同区域B细胞密度呈正相关；而该区域中B细胞密度与肿瘤侵袭边缘的血管生成密切相关，且显著影响肝癌疾病进展（正相关）。以此为基础，本课题拟结合临床样本和实验模型系统研究肝癌中B细胞和IL-21+细胞聚集的机制，分析不同区域B细胞和IL-21+细胞的表型与功能，阐明B细胞和IL-21+细胞功能性相互作用的网络机制；在临床样本中验证相关细胞表型/信号分子与肿瘤血管生成、临床分期和预后的相关性。所得结果将有助于进一步理解肿瘤免疫逃逸的机制，更可为研制以IL-21+和B细胞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。

B细胞是肿瘤间质的重要组分，其分化、成熟以及激活均受组织微环境的紧密调控。近年研究表明：B细胞的活化、增殖及成熟存在T细胞和非T细胞依赖的两种模式，而炎症因子IL-21是T细胞促进B细胞成熟的关键分子，但实体瘤组织中B细胞能否与IL-21+细胞功能性相互作用尚未清楚。本项目研究发现：肝癌组织中B细胞和IL-21+细胞均主要富集于肿瘤侵袭边缘的间质区域。机制研究表明，肝癌组织中CXCR3+ B细胞呈现出往IgG+浆细胞分化的潜能，其聚集和成熟主要受到侵袭边缘上皮细胞来源的CXCL9、CXCL10和CXCL11调控。与此不同，CXCR3− B细胞的成熟主要受到IL-21+细胞的调控，该途径诱导出的浆细胞可产生IgM、IgA和IgG。更有意思的是，我们发现肝癌组织中IL-21主要由CD4+ T辅助细胞产生，而癌旁间质中单核细胞的炎症反应是引起IL-21+ T辅助细胞分化和数量增加的重要原因。临床回顾分析表明IL-21+细胞数量增加是肿瘤患者预后较差的一个独立因素。我们还证实肿瘤中浆细胞，特别是IgG+浆细胞，可显著促进单核细胞往抑制性M2b巨噬细胞极化。可见，实体瘤组织中单核/巨噬细胞、T细胞和B细胞功能性相互作用的网络是导致肿瘤免疫耐受的重要因素。