Abstract While BC has not historically been linked to underlying inflammation or infection, it exhibits tumor-associated inflammation marked by infiltration of innate and adaptive immune cells into developing tumors. In BC, macrophages are one of the most abundant innate immune cells present. BC-associated macrophages are regulated in part by colony stimulating factor 1 (CSF1), a key cytokine involved in monocyte/macrophage maturation, recruitment and activation, and its cognate receptor CSF1R. Macrophage presence in BC correlates with increased CSF1, increased vascular density, and worse clinical outcome. We reported that CD4+ T cells promote invasion and metastasis of mammary adenocarcinomas by directly regulating macrophage phenotype that in turn fosters invasive tumor growth, presence of circulating tumor cells and pulmonary metastasis. This preclinical data implied that women with BC heavily infiltrated by macrophages would have a worse clinical outcome as compared to tumors not heavily infiltrated with macrophages. We evaluated survival outcomes in 698 women with invasive BC treated with surgery alone and found that recurrence-free survival could be stratified based upon macrophage and T cell infiltration. Thus, we investigated CSF1 and CSF1R antagonists, in combination with standard-of-care chemotherapy (CTX) in mouse models of mammary carcinogenesis. We found that when macrophage infiltration in mammary adenocarcinomas was blocked, paclitaxel (PTX) chemosensitivity was increased, accompanied by development of productive anti-tumor immune responses and CD8+ cytotoxic T cell (CTL) infiltration. The combined effects of these changes were reduced primary tumor growth, 85% reduction in metastases and increased survival. In collaboration with clinical colleagues, we are currently evaluating the clinical benefit of macrophage modulation in preclinical models of BC to facilitate biomarker identification, and inform clinical trials of CTX in combination with macrophage-antagonists. Based on our preliminary data, we hypothesize that components of macrophage responses in BC can be identified to serve as biomarkers for risk stratification. And, that these components can be effectively targeted for therapeutic intervention, resulting in reduced late-stage BC development and metastasis when combined with CTX. LMC acknowledges generous support from the NIH/NCI (R01CA130980, R01CA13256, R01CA140943, R01CA15531), the Department of Defense (W81XWH-09-1-0342, W81XWH-10-BCRP-EOHS-EXP) and the Susan G Komen Foundation (KG111084) Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PL2-1.