代谢重编程调控肿瘤相关巨噬细胞的机制和意义

Macrophages (Mφ) are the major component of the tumor microenvironment, and display pro- or anti-tumoral role depends on their local microenvironment. Recently, emerging evidence highlights the predominant role of metabolic reprogramming in regulating macrophage phenotype and plasticity. However, whether and how metabolic changes affect monocyte differentiation towards macrophage in the tumor has not been determined. We have recently observed that in vitro, human hepatocellular tumor-conditioned medium inhibits macrophage development by decreasing their size and granularity, as well as late stage macrophage-related gene expression; meanwhile, we have identified the metabolic phenotype of the Mo/Mφ with reduced mTOR expression, highly fused mitochondrial and elevated glycolytic activity. Based on our preliminary findings, we aim to investigate the tumor infiltrating macrophage maturation status and its clinical significance; elucidate the underlying mechanisms that regulate monocyte-macrophage differentiation through metabolic reprogramming by tumor products; explore the possibility to build anti-tumoral Mφ phenotype by key molecule/pathway manipulation or metabolic repurposing. The results obtained from this project will not only have profound implications for our understanding of Mφ heterogeneity, but also provide new insights into cancer treatment strategy by selectively restoring Mφ’s anti-tumor capacity.

巨噬细胞（Mφ）是肿瘤组织的重要成分，多来源于单核细胞（Mo）的分化并可根据不同的组织微环境呈现出抗/抑肿瘤功能。新近研究发现代谢重编程可显著影响免疫细胞的表型和功能，但目前尚不清楚代谢是否以及如何调控Mo向Mφ的分化。我们在前期研究中观察到：人肝癌细胞系培养上清可显著降低Mo/Mφ的体积、颗粒度以及晚期Mφ相关基因表达，提示肿瘤可抑制Mo向Mφ分化；同时还下调合成代谢关键调控分子mTOR的表达、并增加细胞的糖酵解水平和线粒体融合。以此为基础，本项目拟以肝癌为主要模型，鉴定肿瘤组织中Mo/Mφ的分化状态及其临床意义；阐明肿瘤产物通过代谢重编程对Mo向Mφ分化的影响与潜在调控机制；并探讨通过对关键调控分子和细胞代谢的干预，恢复Mo向Mφ的正常分化及其抗肿瘤活性的可能性。研究结果不仅有助于我们更好地理解肿瘤微环境调控Mφ分化与功能的机制，还将为重建Mφ抗肿瘤功能的治疗策略提供理论基础。

传统的观点认为组织中驻留的巨噬细胞（Mφ）是缺乏增殖能力的终末分化细胞，其来源主要是来自外周血单核细胞（Mos）的迁移和分化。我们在人肝癌组织的癌巢中观察到：肿瘤浸润Mφ具有显著的增殖现象，是组织浸润Mφ的重要来源；这些增殖Mφ的分化程度较低，高表达CD206，呈现免疫抑制的表型，其数量与患者的不良预后相关，并可作为肝癌病人预后判断的独立因素；机制研究发现，Mφ自分泌GM-CSF上调其表面腺苷受体A2A的表达，再协同肿瘤细胞产生的腺苷，通过活化PI3K/Akt和 MEK/ERK 通路来诱导Mφ增殖。进一步探索发现，转录因子C/EBPα对于Mos向Mφ的正常分化至关重要，而肿瘤细胞能通过抑制C/EBPα的表达来抑制Mos向Mφ的正常分化，从而创造低分化状态的Mφ，这些低分化状态的Mφ增殖能力更强，造成了更多Mφ在肝癌组织微环境的聚集，进一步促进了肝癌的进展。这些结果揭示了肿瘤组织中Mφ更新和聚集的新机制，为探讨通过选择性调控组织Mφ数量与功能来重建或恢复其抗肿瘤功能提供理论基础。