巨噬细胞在人体肿瘤不同微环境中的功能表型与调控机制

Macrophages (Mφ) are essential components of host defense in tissues, and under the influence of local conditions, they acquire specialized phenotype with diverse functional programs. Tumor Mφ markedly outnumber other APC and contribute to disease progression in most solid tumor, but the underlying mechanisms are incompletely understood, especially in human tumors. In previous studies, we found that soluble factors derived from tumor cells, including hyaluronan fragments, can alter the normal development of Mφ that is intended to trigger transient early activation of monocytes in the peritumoral region, which in turn induces formation of suppressive Mφ in cancer nests. Notably, the activated monocytes/Mφ in the peritumoral region of hepatocellular carcinoma (HCC) suppressed tumor-specific T cell immunity by expressing B7-H1 molecules, and were significantly superior to the suppressive tumor Mφ in inducing Th17 cell expansion in HCC, which is responsible for the induction of angiogenesis and tissue remodeling. By contrast, high infiltration of monocytes/Mφ in some digestive tract carcinomas is a favorable sign for better clinic outcome. Based on these observations, we will combine the clinical sample analysis and experimental studies to: 1). Examine the phenotype, function and subset of monocytes/Mφ in the different carcinomas from digestive system and their clinical significance; dissect the underlying mechanisms for altered phenotype or selective recruitment of monocytes/Mφ subsets, screen the potential markers for monocytes/Mφ with pro- or anti-tumor activities. 2). Characterize the specific nature of monocytes/Mφ 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 monocytes/Mφ display their anti-tumorigenic or pro-tumorigenic functions in different microenvironment of human tumors, but also provide the molecular basis for the development of Mφ as novel target for cancer prevention and cure.

巨噬细胞（Mφ）是组织中的重要免疫细胞，并可根据局部微环境的变化而展现出多种不同的功能表型。在前一个已结题重点项目等资助下，我们发现：Mφ在同一肝癌组织的不同区域可呈现出独特的表型特征，并通过多种方式来帮助肿瘤进展；而肿瘤可利用单核Mφ在组织中迁移分化的时空特性来对其进行动态教育。我们同时也观察到Mφ在消化道肿瘤组织中的作用与肝癌不同甚至相反。提示：局部组织微环境或肿瘤类型很可能决定了Mφ对肿瘤进展/退化的影响。以此为基础，本课题拟结合临床样本检测和实验模型，来系统的研究/比较：Mφ在不同肿瘤微环境中的表型/功能与细胞亚群构成的差异及其临床意义，筛选并鉴定出2-3个可用来判断Mφ究竟是起着"抗肿瘤"还是"促肿瘤"作用的标记分子；并初步阐明不同肿瘤微环境调控Mφ表型/功能的机制以及影响肿瘤退化/进展的关键因素。为探讨通过调控Mφ表型或细胞亚群趋化来"恢复或重建"其抗肿瘤功能奠定理论基础。

巨噬细胞（Mφ）是组织中的重要免疫细胞，可根据局部微环境的变化而展现出多种不同的功能表型，而对肿瘤进展起着不同的影响，但确切的调控机制（特别是在人体肿瘤组织）尚不清楚。我们发现：1、活化的单核巨噬细胞促进肿瘤进展的新机制：肝癌癌旁间质中活化的Mφ可通过上调CD48分子与NK细胞上的2B4分子相互作用，诱导NK细胞预活化进而引起NK细胞凋亡；PD-L1+Mφ可通过与PD-1分子的相互作用诱导Th17/Th22细胞的扩增，来促进肿瘤的血管生成，募集中性粒细胞并促进其自噬，延长粒细胞的寿命产生促转移蛋白来增加肿瘤细胞的迁移；活化的Mφ同时能诱导内皮细胞上CXCR4的表达，促进血管新生等多种方式来促进肿瘤进展。2、鉴定出多个在组织中起着促/抗肿瘤作用的Mφ新亚群：如肝癌中促肿瘤进展的c-Met+ Mφ亚群能通过促进自分泌MMP9来促进肿瘤转移，而具有抗肿瘤活性的CD169+ Mφ亚群能通过促进Th1/Tc1来产生抗肿瘤效应。胃癌癌巢中高表达IL-25的Mφ，其数量与患者的良好预后相关。3、此外，我们还对组织微环境中Mφ等髓系细胞来源做了初步探讨，发现肿瘤可显著影响外周血造血干/前体细胞的组成和分化偏移，并作为组织中髓系细胞的重要来源。上述结果说明：巨噬细胞受特定肿瘤组织微环境的影响，可通过多种不同的机制来帮助肿瘤进展。此外，除了“促肿瘤”的Mφ外，组织还中存在具有某些具有“抗肿瘤”作用的Mφ亚群。这些发现这将有助于我们以新的思路来探讨免疫编辑在肿瘤进展中的作用，并为探讨通过调控Mφ表型来“恢复或重建”其抗肿瘤功能奠定理论基础。相关结果已有10篇论文发表在J. Clin. Invest., PNAS, Hepatology, J. Hepatol.和J. Pathol.等知名刊物。部分研究成果获2014年度国家自然科学奖二等奖，并入选2016年出版的“国家自然科学基金资助项目优秀成果选编 (六)”。