Tumor-associated macrophages (TAMs) are a heterogeneous population of cells whose phenotypes and functions are shaped by factors that are incompletely understood. Herein, we asked when and where TAMs arise from blood monocytes and how they evolve during tumor development. We initiated pancreatic ductal adenocarcinoma (PDAC) in inducible monocyte fate-mapping mice and combined single-cell transcriptomics and high-dimensional flow cytometry to profile the monocyte-to-TAM transition. We revealed that monocytes differentiate first into a transient intermediate population of TAMs that generates two longer-lived lineages of terminally differentiated TAMs with distinct gene expression profiles, phenotypes, and intratumoral localization. Transcriptome datasets and tumor samples from patients with PDAC evidenced parallel TAM populations in humans and their prognostic associations. These insights will support the design of new therapeutic strategies targeting TAMs in PDAC.

中文翻译：

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时间和位置决定单核细胞的命运及其向肿瘤相关巨噬细胞的转变


肿瘤相关巨噬细胞（TAM）是一种异质细胞群，其表型和功能由尚未完全了解的因素决定。在此，我们询问 TAM 何时何地从血液单核细胞中产生，以及它们在肿瘤发展过程中如何进化。我们在诱导型单核细胞命运图谱小鼠中启动胰腺导管腺癌（PDAC），并结合单细胞转录组学和高维流式细胞术来分析单核细胞到 TAM 的转变。我们发现，单核细胞首先分化为短暂的 TAM 中间群体，产生两个寿命较长的终末分化 TAM 谱系，具有不同的基因表达谱、表型和瘤内定位。 PDAC 患者的转录组数据集和肿瘤样本证明了人类中的平行 TAM 群体及其预后相关性。这些见解将支持针对 PDAC 中 TAM 的新治疗策略的设计。