Transcriptional signatures derived from murine tumor-associated macrophages predict outcome in breast cancer patients

Macrophages are frequently the most abundant immune cells in murine and human cancers. Studies in various transgenic mouse tumor models have revealed pro-tumor functions of tumor-associated macrophages (TAMs), but despite their association with poor clinical outcome in human patients, molecular signatures for the prediction of clinical outcome in humans are still missingbeen demonstrated. Here we generated molecular signatures from F4/80+CD11b+ TAMs from two transgenic breast cancer models: K14cre;Cdh1flox/flox;Trp53flox/flox (KEP), which resembles human invasive lobular carcinoma (ILC) and MMTV-NeuT (NeuT), which resembles HER2-overexpressing breast cancer. Determination of truly specific TAM transcriptome signatures in breast cancer required relationship analysis with healthy mammary gland tissue macrophages (MTMs), since comparison with macrophages from tissues overestimated TAM-specific gene expression. Furthermore, translation of the TAM signatures to outcome prediction in patients required consideration of the breast cancer subtype. TAM signatures derived from the KEP, but not the NeuT model reliably predicted outcome in ILC patients. Collectively, we show that a transgenic mouse tumor model can be utilized to derive a TAM-based signature for human breast cancer outcome prediction and provide a generalizable strategy for determining and applying specific molecular signatures of immune cells to, in principle, any cancer provided the murine model reflects the human disease. Analysis of changes in the expression of mRNAs in tow different murine breast cancer models.

巨噬细胞（macrophages）通常是小鼠和人类癌症中最丰富的免疫细胞。多项针对转基因小鼠肿瘤模型的研究已证实肿瘤相关巨噬细胞（tumor-associated macrophages, TAMs）具备促肿瘤功能；但尽管这类细胞与人类患者的不良临床结局密切相关，目前仍缺乏可用于预测人类临床结局的分子特征谱。本研究从两种转基因乳腺癌模型的F4/80+CD11b+ TAMs中构建了分子特征谱：分别为模拟人类浸润性小叶癌（invasive lobular carcinoma, ILC）的K14cre;Cdh1flox/flox;Trp53flox/flox（KEP）模型，以及模拟人表皮生长因子受体2（HER2）过表达型乳腺癌的MMTV-NeuT（NeuT）模型。若要确定乳腺癌中真正特异性的TAM转录组特征谱，需与健康乳腺组织巨噬细胞（mammary gland tissue macrophages, MTMs）开展关联分析——因为与其他组织来源的巨噬细胞进行比对，会高估TAM特异性基因的表达水平。此外，将TAM特征谱应用于患者的临床结局预测时，需结合乳腺癌的亚型进行综合考量。源自KEP模型的TAM特征谱（而非NeuT模型）可有效预测浸润性小叶癌患者的临床结局。综上，本研究证实可通过转基因小鼠肿瘤模型构建基于TAM的特征谱，用于预测人类乳腺癌的临床结局；同时提供了一套可推广的研究策略：原则上只要小鼠模型能够模拟人类疾病，即可用于确定并将免疫细胞的特异性分子特征谱应用于任意癌症类型。本研究分析了两种不同小鼠乳腺癌模型中mRNA的表达变化情况。