Transcriptional Signatures Derived from Murine Tumor-Associated Macrophages Predict Outcome in Breast Cancer Patients

Abstract

Tumor-associated macrophages (TAMs) are frequently the most abundant immune cells in murine and human cancers and are associated with poor survival. Here we generated TAM molecular signatures from K14cre;Cdh1^flox/flox;Trp53^flox/flox (KEP) and MMTV-NeuT (NeuT) transgenic mice which resemble human invasive lobular carcinoma (ILC) and HER2+ tumors, respectively. Determination of TAM-specific signatures in breast cancer required relationship analysis with healthy mammary tissue macrophages, since comparison with other macrophage populations overestimated TAM-specific gene expression. TAMs from the two models featured a distinct transcriptomic profile and KEP-derived signatures reliably predicted outcome in ILC patients, indicating that translation of murine TAM signatures to patients warrants consideration of the cancer subtype. Collectively, we show that a transgenic mouse tumor model can be utilized to derive a TAM signature for human breast cancer outcome prediction and we provide a generalizable strategy for determining and applying immune cell signatures provided the murine model reflects the human disease.

Keywords: cancer, mouse, human, model, TAM, Macrophage, co-expression network analysis, signature, Transcriptome, innate immunity, breast cancer, tumor-associated macrophages, clinical outcome prediction, invasive lobular carcinoma