Matusiak Magdalena, Hickey John W, Luca Bogdan, Lu Guolan, Kidziński Lukasz, Zhu Shirley, Colburg Deana Rae Crystal, Phillips Darci J, Brubaker Sky W, Charville Gregory W, Shen Jeanne, Nolan Garry P, Newman Aaron M, West Robert B, van de Rijn Matt
Department of Pathology, Stanford University, Stanford, California, USA.
Stanford Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, California, USA.
Res Sq. 2023 Jan 10:rs.3.rs-2393443. doi: 10.21203/rs.3.rs-2393443/v1.
Tumor-associated macrophages (TAMs) display heterogeneous phenotypes. Yet the exact tissue cues that shape macrophage functional diversity are incompletely understood. Here we discriminate, spatially resolve and reveal the function of five distinct macrophage niches within malignant and benign breast and colon tissue. We found that SPP1 TAMs reside in hypoxic and necrotic tumor regions, and a novel subset of FOLR2 tissue resident macrophages (TRMs) supports the plasma cell tissue niche. We discover that IL4I1 macrophages populate niches with high cell turnover where they phagocytose dying cells. Significantly, IL4I1 TAMs abundance correlates with anti-PD1 treatment response in breast cancer. Furthermore, NLRP3 inflammasome activation in NLRP3 TAMs correlates with neutrophil infiltration in the tumors and is associated with poor outcome in breast cancer patients. This suggests the NLRP3 inflammasome as a novel cancer immunetherapy target. Our work uncovers context-dependent roles of macrophage subsets, and suggests novel predictive markers and macrophage subset-specific therapy targets.
肿瘤相关巨噬细胞（TAM）表现出异质性表型。然而，塑造巨噬细胞功能多样性的确切组织线索尚未完全明确。在此，我们区分、在空间上解析并揭示了恶性和良性乳腺及结肠组织中五个不同巨噬细胞生态位的功能。我们发现SPP1 TAM存在于缺氧和坏死的肿瘤区域，并且一个新的FOLR2组织驻留巨噬细胞（TRM）亚群支持浆细胞组织生态位。我们发现IL4I1巨噬细胞聚集在细胞更新率高的生态位中，在那里它们吞噬死亡细胞。值得注意的是，IL4I1 TAM的丰度与乳腺癌中抗PD1治疗反应相关。此外，NLRP3 TAM中的NLRP3炎性小体激活与肿瘤中的中性粒细胞浸润相关，并与乳腺癌患者的不良预后相关。这表明NLRP3炎性小体是一种新的癌症免疫治疗靶点。我们的工作揭示了巨噬细胞亚群的背景依赖性作用，并提出了新的预测标志物和巨噬细胞亚群特异性治疗靶点。
