美国斯隆凯特琳学院教授李明研究组探明，重编程肿瘤相关巨噬细胞(TAMs)战胜血管内皮祖细胞并抑制肿瘤新生血管生成。2023年11月14日，国际知名学术期刊《免疫》发表了这一成果。

在乳腺癌的转基因模型中，他们发现TAM定位于肿瘤实质，并且比乳腺组织巨噬细胞小。TAM具有低活性的代谢调节哺乳动物/机制靶雷帕霉素复合物1 (mTORC1)，并且在TAM中，mTORC1信号的负调节物结节硬化复合物1 (TSC1)的消耗以不依赖于适应性淋巴细胞的方式抑制肿瘤生长。野生型TAM具有炎症和血管生成基因表达谱，而TSC1缺陷TAM具有促溶解表型。

缺乏TSC1的TAM迁移到血管周围生态位，耗尽表达血管内皮祖细胞的蛋白C受体(PROCR)，纠正高通透性的血管系统，导致肿瘤组织缺氧和癌细胞死亡。在细胞竞争实验中，缺乏TSC1的TAM具有代谢活性，并有效地消除了表达PROCR的内皮细胞。因此，TAM表现出TSC1依赖的mTORC1低状态，mTORC1信号的增加促进了抑制肿瘤生长的促分解状态，定义了一种可能用于癌症免疫治疗的先天免疫肿瘤抑制途径。

据介绍，肿瘤是通过激活以异常血管生成和TAM浸润为特征的支持性环境而发展的。

附：英文原文

Title: Reprogramming tumor-associated macrophages to outcompete endovascular endothelial progenitor cells and suppress tumor neoangiogenesis

Author: Mytrang H. Do, Wei Shi, Liangliang Ji, Erik Ladewig, Xian Zhang, Raghvendra M. Srivastava, Kristelle J. Capistrano, Chaucie Edwards, Isha Malik, Briana G. Nixon, Efstathios G. Stamatiades, Ming Liu, Shun Li, Peng Li, Chun Chou, Ke Xu, Ting-Wei Hsu, Xinxin Wang, Timothy A. Chan, Christina S. Leslie, Ming O. Li

Issue&Volume: 2023/11/14

Abstract: Tumors develop by invoking a supportive environment characterized by aberrant angiogenesisand infiltration of tumor-associated macrophages (TAMs). In a transgenic model ofbreast cancer, we found that TAMs localized to the tumor parenchyma and were smallerthan mammary tissue macrophages. TAMs had low activity of the metabolic regulatormammalian/mechanistic target of rapamycin complex 1 (mTORC1), and depletion of negativeregulator of mTORC1 signaling, tuberous sclerosis complex 1 (TSC1), in TAMs inhibitedtumor growth in a manner independent of adaptive lymphocytes. Whereas wild-type TAMsexhibited inflammatory and angiogenic gene expression profiles, TSC1-deficient TAMshad a pro-resolving phenotype. TSC1-deficient TAMs relocated to a perivascular niche,depleted protein C receptor (PROCR)-expressing endovascular endothelial progenitorcells, and rectified the hyperpermeable blood vasculature, causing tumor tissue hypoxiaand cancer cell death. TSC1-deficient TAMs were metabolically active and effectivelyeliminated PROCR-expressing endothelial cells in cell competition experiments. Thus,TAMs exhibit a TSC1-dependent mTORC1-low state, and increasing mTORC1 signaling promotesa pro-resolving state that suppresses tumor growth, defining an innate immune tumorsuppression pathway that may be exploited for cancer immunotherapy.

DOI: 10.1016/j.immuni.2023.10.010

Source: https://www.cell.com/immunity/fulltext/S1074-7613(23)00451-X