巨噬细胞在肿瘤组织中增殖的调控机制与临床意义

Macrophage (Mφ) are essential components of host defense and act as both antigen presenting cells and effector cells. Mφ constitutes a major component of most solid tumors, and can play pro- and anti-tumoral roles under the influence of local micro-environments. Tissue Mφ have long been considered as terminally-differentiated cells. However, emerging evidence indicates that these cells were capable of proliferating and self-renewal. Although proliferating Mφ were shown to influence the disease outcome, their phenotypes, functions and regulating mechanisms are still poorly understood, particularly in human. We have recently observed that Mφ exhibited significant proliferating activity in tumor tissues and both the absolute numbers and percentage of proliferating Mφ were markedly higher in tumors than those in paired non-tumor tissues. Proliferating Mφ in human hepatocellular carcinoma (HCC) tissues displayed distinct phenotypes which differs from their counterparts reported in mouse model, and their levels showed significant negative correlation with patient prognosis. Based on these findings, we will combine experimental studies and clinical sample analysis, 1) To investigate the distribution, phenotype and clinical significance of Mφ proliferation. 2) To study the underlying mechanisms and define the key molecules/pathways that regulate Mφ proliferation in human tumors, with emphasis on tumor cell-derived factors/components and altered metabolic pathways in consideration of the nutrition insufficient characteristics of tumor microenvironments. 3) To explore the contribution and regulating mechanisms of Mφ proliferation in the formation of tumor immune environment and their potential impact on targeted anti-tumor therapies. The results obtained from this project would not only reveal the novel mechanisms about the accumulation and replenishment of Mφ in human tumors, but would also provide the molecular basis for “restore” the anti-tumor immune microenvironments by selective modulating the accumulation and balance of different Mφ subgroups.

巨噬细胞（Mφ）是肿瘤组织的重要成分，可根据不同的微环境呈现出抗/抑肿瘤功能。传统认为Mφ是缺乏增殖能力的终末分化细胞，然而新近研究表明组织Mφ具有自我更新能力，但关于它们的表型功能及调控机制目前尚不清楚。我们最近观察到Mφ在人肝癌组织中存在增殖现象，且在癌巢中的比例显著上调。这些增殖的Mφ具有与文献（小鼠肿瘤模型）不一致的表型特征，并与患者的不良预后显著相关。以此为基础，本项目拟以肝癌为主要模型，结合临床样本分析和实验模型，来明确肿瘤组织中增殖Mφ的分布、表型、来源及其临床意义。以组织营养缺乏与肿瘤细胞来源成分为切入点，初步阐明肿瘤组织调控Mφ增殖的代谢机制并鉴定出1-2个关键分子/通路。并进一步研究增殖Mφ与其它免疫细胞相互作用的网络机制以及对靶向治疗的可能影响。所得结果将有助于阐明肿瘤组织中Mφ更新和聚集的机制，并为探讨通过调控组织Mφ数量与功能来重建或恢复其抗肿瘤功能提供理论基础。

传统认为组织中的巨噬细胞（Mφ）是缺乏增殖能力的终末分化细胞，然而新近研究表明Mφ具有自我更新能力，但关于它们在肿瘤中的表型功能及调控机制目前尚不清楚。我们发现：1、肿瘤浸润Mφ在组织原位增殖和存活的新机制：癌巢组织中的Mφ存在显著的增殖。这些增殖的Mφ呈现出免疫抑制表型并与患者的不良预后相关。肿瘤细胞一方面通过其表面的CD73分子来产生腺苷；同时通过诱导单核Mφ自分泌GM-CSF，上调Mφ表面腺苷受体A2A的表达，进而协同促进Mφ增殖和疾病进展。此外，我们还发现肿瘤相关Mφ选择性高表达碳酸酐酶XII (CA12)，提高了Mφ在酸性环境中的生存能力和促肿瘤作用。2、代谢重塑调控肿瘤相关Mφ免疫特性及促肿瘤侵袭转移新机制：肝癌组织微环境能够诱导单核细胞上调糖酵解通路，表达PD-L1来产生免疫抑制；以及募集中性粒细胞，促进肝癌进展。还可上调侵袭前沿区域肿瘤细胞的自噬水平，促进肿瘤侵袭转移。3、抑制型髓系细胞产生的新机制及其临床意义：荷瘤宿主脾脏通过CCL2/CCR2趋化轴从外周血中募集特定的造血干/前体细胞（HSPC）亚群，对其进行“重编程”来产生具有更强免疫抑制功能的MDSC；并探讨了在肿瘤组织微环境中，髓系前体细胞扩增并成为具有免疫抑制功能MDSC的机制，以及MDSC对疾病疾病进展和ICB治疗应答的影响于调控机制。4、构建出只需CD169和CD11b 2个髓系标记的“髓系反应评分”系统，该系统能反映肝癌组织浸润的髓系细胞亚群的变化、免疫微环境内涵，指征患者预后以及对治疗的应答的。上述系列结果揭示了：Mφ等髓系细胞在肿瘤组织中聚集和功能调控的机制，以及对疾病进展和治疗应答的影响。通过选择性干预肿瘤组织中髓系细胞的生成、发育、扩增与存活，可使组织免疫微环境向“抗肿瘤”方向倾斜并发展成为肿瘤免疫治疗的新策略。相关结果已有14篇标注论文发表在J. Clin. Invest., J. Hepatol., 和Autophagy等知名刊物。部分研究成果获2018年度教育部高校科研优秀成果奖一等奖。