Genomics and Immunoregulation, LIMES Institute, University of Bonn, 53113 Bonn, Germany; Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands.
Division of Tumor Biology & Immunology, Oncode Institute, the Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
Cell Rep. 2019 Oct 29;29(5):1221-1235.e5. doi: 10.1016/j.celrep.2019.09.067.
Tumor-associated macrophages (TAMs) are frequently the most abundant immune cells in cancers and are associated with poor survival. Here, we generated TAM molecular signatures from K14cre;Cdh1;Trp53 (KEP) and MMTV-NeuT (NeuT) transgenic mice that resemble human invasive lobular carcinoma (ILC) and HER2 tumors, respectively. Determination of TAM-specific signatures requires comparison with healthy mammary tissue macrophages to avoid overestimation of gene expression differences. TAMs from the two models feature a distinct transcriptomic profile, suggesting that the cancer subtype dictates their phenotype. The KEP-derived signature reliably correlates with poor overall survival in ILC but not in triple-negative breast cancer patients, indicating that translation of murine TAM signatures to patients is cancer subtype dependent. Collectively, we show that a transgenic mouse tumor model can yield a TAM signature relevant for human breast cancer outcome prognosis and provide a generalizable strategy for determining and applying immune cell signatures provided the murine model reflects the human disease.
肿瘤相关巨噬细胞（TAMs）通常是癌症中最丰富的免疫细胞，与预后不良有关。在这里，我们从 K14cre;Cdh1;Trp53（KEP）和 MMTV-NeuT（NeuT）转基因小鼠中生成了类似于人类浸润性小叶癌（ILC）和 HER2 肿瘤的 TAM 分子特征，分别。确定 TAM 特异性特征需要与健康乳腺组织巨噬细胞进行比较，以避免高估基因表达差异。两种模型的 TAMs 具有独特的转录组特征，表明癌症亚型决定了它们的表型。KEP 衍生的特征与 ILC 患者的总体生存率差相关，但与三阴性乳腺癌患者无关，表明将鼠 TAM 特征转化为患者是依赖于癌症亚型的。总之，我们表明，转基因小鼠肿瘤模型可以产生与人类乳腺癌预后相关的 TAM 特征，并提供了一种可用于确定和应用免疫细胞特征的可推广策略，前提是该鼠模型反映了人类疾病。
