Dexamethasone drives macrophage repolarization linked to increased triple-negative breast cancer aggressiveness

Glucocorticoids (GCs) are known for their anti-inflammatory potential, which includes the macrophage polarization into an anti-inflammatory and tissue remodeling state. GCs are routinely co-administered to Cancer patients to alleviate the side effects of chemotherapy. However, it is not well known if GCs can modulate tumor-associated Macrophages (TAMs) to promote tumor progression. Here, we show that dexamethasone (DEX) induces dose-dependent differentiation of THP-1 monocyte-derived anti-tumorigenic (M1) Macrophages into pro-tumorigenic (M2-like) Macrophages, even in the presence of M1 cues, and that DEX can repolarize fully differentiated M1 Macrophages into an M2-like state. These Macrophages have a cytokine profile similar to the pro-tumorigenic (M2) Macrophages and can stimulate the proliferation and invasion of Triple-Negative Breast Cancer (TNBC) cells in vitro. DEX treatment of an orthotopic mouse model of TNBC attenuated paclitaxel-mediated tumor growth inhibition, increased M2-like TAMs in primary Tumors, and enhanced lung metastasis. Transcriptomic analysis of DEX-treated M1 Macrophages revealed not only transcriptomic overlap with M2 Macrophages, but also with human Breast Cancer TAM transcriptomic data, and further to a specific TAM signature associated with aggressive estrogen receptor-negative Breast Cancer. Our study illustrates a remarkable macrophage repolarization plasticity upon DEX exposure that can promote tumorigenesis, warranting care in prescribing high doses of GCs to Breast Cancer patients, especially to those considered for chemotherapy.