Transcriptional Signature Derived from Murine Tumor-Associated Macrophages Correlates with Poor Outcome in Breast Cancer Patients

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;Cdh1flox/flox;Trp53flox/flox (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. [Display omitted] •Murine TAM signatures prognosticate outcomes in corresponding cancer patients•TAM signatures are robust when they are compared with healthy tissue macrophages•TAM transcriptome is dictated by tissue and tumor subtype-related signals•Murine TAM signatures can be translated only when a suitable model is chosen Tuit et al. show that TAM transcriptomes in murine models of breast cancer are governed mainly by tissue and tumor subtype-specific signals. Clinical translation of murine signatures can be achieved when human and mouse breast tumor subtypes are matched and only upon proper comparison of TAMs with healthy tissue macrophages.