肿瘤相关粒细胞调控浆细胞分化和功能的机制研究

Neutrophils constitute an important component of the leukocyte infiltrate in the tumor stroma. However, knowledge about tumor-associated neutrophils has just begun to be unveiled. In the support of previous project grants from NSFC (81000915), we found that the pro-inflammatory response in tumors in situ was critical for the recruitment of neutrophils into peritumoral stroma of hepatocellular carcinoma. Under the in?uence of tumor environments, these neutrophils acquired specialized phenotypic characteristics with increased autophagy, and they subsequently promoted tumor progression by fostering metastasis. Recently, we also observed a co-localization of neutrophils and plasma cells in the tumor areas of several types of human cancers; and tumor-derived neutrophils could stimulate B cells differentiation into plasma cells ex vivo. Based on these findings, we will combine the clinical sample analysis and experimental studies to: 1). Examine the phenotype, function and subset of neutrophils in the different carcinomas from digestive system and their clinical significance; dissect the underlying mechanisms for altered phenotype of neutrophils, screen the potential markers for neutrophils with activities to trigger plasma cell differentiation. 2). Characterize the specific nature of plasma cells context that determine their ability to facilitate or prevent tumor growth. 3). Define the key molecules/markers that regulate the development of human tumors with paired tissue sample collected from different stages of disease progression. The results obtained from this project will not only reveal the molecular mechanisms about how neutrophils and plasma cells display their pro-tumorigenic functions in different environment of human tumors, but also provide the molecular basis for the development of neutrophils and plasma cells as novel targets for cancer prevention and cure.

粒细胞（PMN）是肿瘤间质的重要组分，但目前对于肿瘤相关PMN的认识仍处于初级阶段并主要是基于动物实验的结果。在刚结题的青年科学基金资助下，我们以人肝癌为主要模型，发现：实体瘤利用促炎症反应来招募PMN，使其富集于侵袭边缘；新募集的PMN受微环境教育获得高自噬表型，并通过多种途径促进肿瘤转移。我们同时也观察到：肝癌和多种消化道肿瘤中PMN与浆细胞分布较为一致，而且来源于肝癌组织的PMN能有效刺激B淋巴细胞分化成浆细胞。以此为基础，本课题拟以人消化系统肿瘤为主要模型来系统的研究：实体瘤中PMN的亚群构成及其表型/功能，筛选出2-3个由PMN产生并可调控B淋巴细胞往浆细胞分化的主要成分及阐明其潜在信号机制；在临床样本中验证相关表型/信号分子与血管生成、临床分期和预后的相关性；初步阐明浆细胞影响肿瘤退化/进展的关键因素，为研制以PMN和浆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。

中性粒细胞（PMN）、B细胞和浆细胞均是人肿瘤间质的重要组分，但目前关于这些细胞功能性相互作用的机制仍未清楚。在本面上项目的资助下，我们以人肝癌为主要模型，发现：1）肿瘤微环境通过诱导自噬发生来维持PMN的生存和促肿瘤功能；2）这些持续生存的PMN通过NET的方式来释放出胞内DNA和PR3蛋白，继而诱导B细胞分化成熟并产生针对PR3蛋白的自身抗体；3）肿瘤中IgG型的自身抗体可通过结合到巨噬细胞表面的Fc受体，进一步诱导促肿瘤巨噬细胞的形成，随后削弱抗肿瘤T细胞的免疫应答。除此之外，我们还深入研究了肿瘤中其它B细胞亚群的组成和功能。结果显示：B细胞不仅可以分化成熟为浆细胞，也可在肿瘤微环境影响下分化为可产生大量IL-10的新型调节性B细胞，它们可呈现为PD-1high或FcγRIIlow的表型。上述的系列率先揭示了B细胞免疫反应网络在人实体瘤进展中的重要性：B细胞一方面利用其体液免疫反应特征来诱导促肿瘤髓系细胞形成，同时还分化成多个具调节性功能的细胞亚群来直接抑制了T细胞的抗肿瘤免疫应答，最终加快肿瘤的恶性进展。靶向B细胞浸润或抑制浆细胞分化将有望恢复宿主的抗肿瘤免疫应答。