Amgen Research, Oncology , South San Francisco, CA, USA.
Department of Genetics, Stanford University School of Medicine , Stanford, CA, USA.
J Exp Med. 2023 Jun 5;220(6). doi: 10.1084/jem.20221472. Epub 2023 Mar 30.
Phagocytosis is a key macrophage function, but how phagocytosis shapes tumor-associated macrophage (TAM) phenotypes and heterogeneity in solid tumors remains unclear. Here, we utilized both syngeneic and novel autochthonous lung tumor models in which neoplastic cells express the fluorophore tdTomato (tdTom) to identify TAMs that have phagocytosed neoplastic cells in vivo. Phagocytic tdTompos TAMs upregulated antigen presentation and anti-inflammatory proteins, but downregulated classic proinflammatory effectors compared to tdTomneg TAMs. Single-cell transcriptomic profiling identified TAM subset-specific and common gene expression changes associated with phagocytosis. We uncover a phagocytic signature that is predominated by oxidative phosphorylation (OXPHOS), ribosomal, and metabolic genes, and this signature correlates with worse clinical outcome in human lung cancer. Expression of OXPHOS proteins, mitochondrial content, and functional utilization of OXPHOS were increased in tdTompos TAMs. tdTompos tumor dendritic cells also display similar metabolic changes. Our identification of phagocytic TAMs as a distinct myeloid cell state links phagocytosis of neoplastic cells in vivo with OXPHOS and tumor-promoting phenotypes.
吞噬作用是巨噬细胞的关键功能，但吞噬作用如何塑造实体瘤中肿瘤相关巨噬细胞（TAM）的表型和异质性仍不清楚。在这里，我们利用了同源和新型的自发肺肿瘤模型，其中肿瘤细胞表达荧光蛋白 tdTomato（tdTom），以鉴定体内吞噬肿瘤细胞的 TAM。与 tdTomneg TAMs 相比，吞噬性 tdTompos TAMs 上调了抗原呈递和抗炎蛋白，但下调了经典的促炎效应因子。单细胞转录组谱分析确定了与吞噬作用相关的 TAM 亚群特异性和常见的基因表达变化。我们揭示了一个吞噬作用特征，主要由氧化磷酸化（OXPHOS）、核糖体和代谢基因组成，该特征与人类肺癌的临床预后较差相关。tdTompos TAMs 中 OXPHOS 蛋白的表达、线粒体含量和 OXPHOS 的功能利用增加。tdTompos 肿瘤树突状细胞也表现出类似的代谢变化。我们将吞噬性 TAMs 鉴定为一种独特的髓样细胞状态，将体内肿瘤细胞的吞噬作用与 OXPHOS 和促进肿瘤的表型联系起来。
