Pedroza, D. A.; Yuan, X.; Liu, F.; Chan, H. L.; Zhang, C.; Bowie, W.; Smith, A. J.; Calderon, S. J.; Lieu, N.; Wu, W.; Porter, P.; Sarkar, P.; Zhao, N.; Oehler, C. V.; Peller, O.; Gaber, M. W.; Zhu, Q.; perou, c.; Zhang, X.; Rosen, J.

Patients diagnosed with metastatic triple negative breast cancer (mTNBC) have limited treatment options, are more prone to develop resistance and are associated with high mortality. A cold tumor immune microenvironment (TIME) characterized by low T cells and high tumor associated macrophages (TAMs) in mTNBC is associated with the failure of standard-of-care chemotherapy and immune checkpoint blockade (ICB) treatment. We demonstrate that the combination of immunomodulatory metronomic Cyclophosphamide (CTX) coupled with anti-CSF-1R antibody targeted therapy (SNDX-ms6352) and anti-PD-1 (ICB), was highly effective against aggressive metastatic syngeneic Trp53 null TNBC genetically engineered mouse models (GEMMs) that present with high macrophage infiltration. Mechanistically, CSF-1R inhibition along with CTX disrupted the M-CSF/CSF-1R axis which upregulated IL-17, IL-15 and type II interferon resulting in elevated B- and T cell infiltration. Addition of an anti-PD-1 maintenance dose helped overcome de novo PD-L1 intra-tumoral heterogeneity (ITH) associated recurrence in lung and liver mTNBC.