Human Tumor-Associated Macrophage and Monocyte Transcriptional Landscapes Reveal Cancer-Specific Reprogramming, Biomarkers, and Therapeutic Targets. Human Tumor-Associated Macrophage and Monocyte Transcriptional Landscapes Reveal Cancer-Specific Reprogramming, Biomarkers, and Therapeutic Targets

The roles of tumor-associated macrophages (TAMs) and circulating monocytes in human cancer are poorly understood. Here, we show that monocyte subpopulation distribution and transcriptomes are significantly altered by the presence of endometrial and breast cancer. Furthermore, TAMs from endometrial and breast cancers are transcriptionally distinct from monocytes and their respective tissue-resident macrophages. We identified a breast TAM signature that is highly enriched in aggressive breast cancer subtypes and associated with shorter disease-specific survival. We also identified an auto-regulatory loop between TAMs and cancer cells driven by tumor necrosis factor alpha involving SIGLEC1 and CCL8, which is self- reinforcing through the production of CSF1. Together these data provide direct evidence that monocyte and macrophage transcriptional landscapes are perturbed by cancer, reflecting patient outcomes. Overall design: RNA-seq of purified human circulating monocytes and tumor-associated macrophages (TAMs) in breast and endometrial cancers.

肿瘤相关巨噬细胞（tumor-associated macrophages, TAMs）与循环单核细胞在人类癌症中的作用尚未得到充分阐明。本研究证实，子宫内膜癌与乳腺癌的存在会显著改变单核细胞亚群的分布及其转录组特征。进一步研究发现，子宫内膜癌与乳腺癌来源的TAMs在转录谱上，既区别于循环单核细胞，也与其对应的组织驻留巨噬细胞存在显著差异。我们鉴定出一套乳腺TAM特征基因集，该特征在侵袭性乳腺癌亚型中高度富集，且与更短的疾病特异性生存期相关。此外，我们还发现了一条由肿瘤坏死因子α（tumor necrosis factor alpha）介导的TAMs与癌细胞间的自调控环路，该环路涉及SIGLEC1与CCL8，并通过集落刺激因子1（colony-stimulating factor 1, CSF1）的产生实现自我强化。综上，本研究提供了直接实验证据，证明癌症可扰乱单核细胞与巨噬细胞的转录调控图谱，且该变化与患者的临床结局密切相关。实验整体设计：对纯化的人循环单核细胞以及乳腺癌与子宫内膜癌患者的肿瘤相关巨噬细胞（TAMs）进行RNA测序（RNA-seq）。