肿瘤相关单核巨噬细胞表型与功能的代谢调控机制

Metabolic reprogramming is one of the major characteristics of cancer. While most studies laid their focus on metabolic changes in tumor cell itself, the possible metabolic characteristics of tumor-infiltrating monocytes/macrophages (Mφ) are not so clear. Our recent study found that glycolysis was significantly up-regulated on Mφ isolated from tumor tissues of patients with hepatocarcinoma (HCC), and these Mφ with high glycolytic rate was mainly infiltrated in the peritumoral stroma of HCC. In vitro experiments showed that glycolysis was involved in the regulation of specific cytokine secretion by tumor associated Mφ. Therefore, such metabolic changes might represent novel functional markers and therapeutic targets for Mφ in specific tumor microenvironments. To confirm this hypothesis, we will combine experimental studies and clinical sample analysis to: 1) Examine the metabolic phenotypes and clinical significance of Mφ isolated from human HCC samples; 2) Explore the possible role of glycolysis or related pathways in regulating the phenotype and functions of Mφ; 3) Define key molecules and signaling pathways regulating the activation/accumulation of glycolysis/specific metabolites in Mφ infiltrating specific tumor microenvironments; 4) Confirm the relative mechanisms obtained through the above experiments in mouse model and clinical samples, and explore the possible impact on therapeutic responses. The prospective results would not only help to unveil a novel mechanism of tumor immune editing, but would also contribute to the reconstitution of anti-tumor function of Mφ, as well as the rational design of therapies targeting both the tumor and immune components.

代谢失衡是肿瘤的重要生物学特征之一。目前对于组织微环境中单核巨噬细胞（Mφ）的代谢特征及其相关调控机制尚未完全清楚。我们最近的研究结果发现，肝癌病人肿瘤组织中分选得到的Mφ显著上调了糖酵解代谢水平；且糖酵解的上调能够特异性调控Mφ分泌TNF-a，IL-10等细胞因子的功能。提示：特定的代谢方式能够调控局部微环境中Mφ的表型与功能，可能代表了一类新型的肝癌诊断/治疗靶标。以此为基础，本项目拟以肝癌为主要模型：分析正常肝组织与肝癌组织中Mφ的代谢特性及临床意义；建立体外实验模型，探讨特定代谢通路/分子调控Mφ促/抑肿瘤功能的相关机制；根据前面结果，进一步探讨肿瘤微环境调控Mφ特定代谢功能的具体方式；最后结合临床样本和小鼠模型验证相关机制，并探讨对临床诊断及治疗应答的可能影响与意义。所得结果将为重建/恢复特定组织微环境中Mφ的抗肿瘤功能、筛选同时靶向免疫细胞与肿瘤细胞的新型药物提供新的思路。

代谢失衡是肿瘤的重要生物学特征之一。目前对于组织微环境中单核巨噬细胞（Mφ）的代谢特征及其相关调控机制尚未完全清楚。在本项目的支持下，我们以肝癌为主要模型，探讨了肿瘤相关单核巨噬细胞表型与功能的代谢调控机制。研究结果包括：1）发现了单核细胞通过代谢重塑、分泌各种细胞因子、调控自身细胞表面活化/抑制型分子的表达与平衡，促进T细胞的失能与肿瘤免疫逃逸的新机制（2019 J Hepatol，共通排最后，IF 20.5；2021 Mol Ther，共通排最后，IF 11.4；2020 Hepatol Int，独立通讯，IF 6.0）。2）揭示了活化单核细胞通过调控中性粒细胞的聚集与功能，促进肿瘤转移新机制（2020 J Hepatol，独立通讯，IF 25.0）。3）阐明了活化单核细胞通过诱导肿瘤自噬、促进肿瘤转移的新机制（2018 Autophagy，共通排2，IF 11.0）。这些结果不仅有助于我们更好地理解肿瘤的免疫逃逸与编辑机制，更为肝癌的临床诊断与治疗提供了潜在的新型靶标分子。