B细胞在不同消化系统肿瘤中亚群和功能差异的机制

We and others have previously shown that the infiltrated immune cells and cytokines could exhibit distinct phenotype and distribution patterns in human tumors originated from liver and digestive tract, and thus have differential or even opposing impact on disease progression. B cells are prominent immune components of solid tumors, but their function and regulation are still largely unknown. We recently observed that several types of B cells were recruited or induced by hepatoma microenvironments and subsequently promoted disease progression. In contrast, these identified protumorigenic B cells were reduced and even lacking in colorectal cancer. B cell majority exhibited functions that inhibited colorectal cancer progression. These results indicate that the local conditions from different cancer microenvironments may influence the accumulation and functional programs of B cells. Based on these findings, we will combine the clinical sample analysis and experimental studies to: 1) characterize the accumulation, composition and functional activities of B cell subsets in both liver cancer and colorectal tumor tissues, and dissect the underlying mechanisms; 2) screen and define the key subsets and signaling molecules that may have significant impact on the progression or degeneration of liver or colorectal cancer; 3) evaluate the effectiveness on tumor progression by selectively regulating the recruitment and differentiation of B cell subset in liver colorectal tumor tissues. The results obtained from this project will not only reveal the molecular mechanisms by which tumor induce the generation of B cell subset, but also provide the molecular basis for the development of B cells as novel target for cancer prevention and cure.

我们在前期已观察到：在肝癌和消化道肿瘤组织中，多种免疫细胞或因子可呈现出各自独特的表型与分布，并对疾病进展起着不同甚至相反的作用。B细胞是肿瘤组织中数量丰富但亚群/功能研究非常空白的重要免疫细胞。我们新近发现：肝癌组织微环境主动募集或诱导出多个具“促肿瘤”活性的B细胞亚群来促进疾病进展。但是相关促肿瘤亚群在肠癌组织减少甚至缺乏，B细胞主要起限制肠癌进展的作用。提示：不同肿瘤组织微环境对B细胞亚群募集、极化以及功能有不同的影响机制。本课题拟结合人体样本检测和实验模型，来系统的研究/比较：B细胞在肝癌与肠癌组织微环境中聚集、亚群极化与功能的差异与调控机制；筛选并鉴定出可用于判断肝癌和肠癌进展/退化的B细胞亚群或功能分子；并探讨选择性调控B细胞在组织中聚集与分化的可行性以及对肿瘤进展的影响；为肿瘤免疫治疗提供新的思路和干预靶点。

B细胞是人体肿瘤组织数量丰富重要免疫细胞，但其在肿瘤进展/退化过程中的作用仍未清楚。我们在前期研究发现：肝癌组织微环境主动募集或诱导出多个具“促肿瘤”活性的B细胞亚群来促进疾病进展。但是相关促肿瘤亚群在肠癌组织减少甚至缺乏。提示：不同肿瘤组织微环境对B细胞亚群募集、极化以及功能有不同的影响机制。在重大研究计划培育项目的资助下，我们以人消化系统肿瘤为主要研究模型，开展了B细胞亚群及其功能差异的机制研究，发现：1）不同消化系统肿瘤中B细胞亚群组成和功能显著差异，肝癌组织中主要存在促肿瘤的B细胞亚群，而肠癌和鼻咽癌组织中主要存在抗肿瘤的B细胞亚群。2）肝癌和肠癌组织分别浸润大量可分泌IgG和IgA的浆细胞，其中IgG阳性浆细胞的募集及成熟受到局部微环境巨噬细胞调控；肿瘤中单核/巨噬细胞通过选择性的分泌CXCL10来招募并刺激CXCR3阳性B细胞成熟为可分泌IgG的浆细胞。3）IgG阳性浆细胞可进一步诱导M2b巨噬细胞形成；M2b巨噬细胞一方面通过诱导效应T细胞失能来废除表观遗传重塑治疗的疗效，同时通过诱导PD-L1阳性肿瘤细胞来削弱免疫检查点治疗的疗效。4）多种消化系统肿瘤组织中炎性T辅助细胞亚群（Th1、Th17、Th22等）显著增多；初始型B细胞可以通过ICOSL依赖的方式促进记忆性T辅助细胞糖酵解上调，继而促使这些细胞分化成产生IL-17、IL-22和IFN-γ的亚群，最终导致局部恶性炎症发生。项目的研究发现在国际上率先揭示了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改变髓系反应的方向，同时还能显著影响T细胞的炎症反应，最终影响肿瘤进展/退化。