Department of Pathology, Stanford University, Stanford, California.
Department of Bioengineering, Stanford University, Stanford, California.
Cancer Discov. 2024 Aug 2;14(8):1418-1439. doi: 10.1158/2159-8290.CD-23-1300.
Tumor-associated macrophages are transcriptionally heterogeneous, but the spatial distribution and cell interactions that shape macrophage tissue roles remain poorly characterized. Here, we spatially resolve five distinct human macrophage populations in normal and malignant human breast and colon tissue and reveal their cellular associations. This spatial map reveals that distinct macrophage populations reside in spatially segregated micro-environmental niches with conserved cellular compositions that are repeated across healthy and diseased tissue. We show that IL4I1+ macrophages phagocytose dying cells in areas with high cell turnover and predict good outcome in colon cancer. In contrast, SPP1+ macrophages are enriched in hypoxic and necrotic tumor regions and portend worse outcome in colon cancer. A subset of FOLR2+ macrophages is embedded in plasma cell niches. NLRP3+ macrophages co-localize with neutrophils and activate an inflammasome in tumors. Our findings indicate that a limited number of unique human macrophage niches function as fundamental building blocks in tissue. Significance: This work broadens our understanding of the distinct roles different macrophage populations may exert on cancer growth and reveals potential predictive markers and macrophage population-specific therapy targets.
肿瘤相关巨噬细胞在转录上具有异质性，但形成巨噬细胞组织功能的空间分布和细胞相互作用仍知之甚少。在这里，我们在正常和恶性人类乳腺和结肠组织中空间解析了五个不同的人类巨噬细胞群体，并揭示了它们的细胞关联。这个空间图谱揭示了不同的巨噬细胞群体存在于空间上分隔的微环境龛中，具有保守的细胞组成，在健康和患病组织中重复出现。我们表明，IL4I1+巨噬细胞在细胞更新率高的区域吞噬死亡细胞，并预测结肠癌预后良好。相比之下，SPP1+巨噬细胞在缺氧和坏死的肿瘤区域富集，并预示着结肠癌预后不良。一小部分 FOLR2+巨噬细胞嵌入浆细胞龛中。NLRP3+巨噬细胞与中性粒细胞共定位，并在肿瘤中激活炎症小体。我们的研究结果表明，有限数量的独特人类巨噬细胞龛作为组织的基本构建块发挥作用。意义：这项工作拓宽了我们对不同巨噬细胞群体在癌症生长中可能发挥的不同作用的理解，并揭示了潜在的预测标志物和巨噬细胞群体特异性治疗靶点。
