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Anti-CSF-1R therapy with combined immuno- chemotherapy coordinate an adaptive immune response to eliminate macrophage enriched Triple Negative Breast Cancers

ABSTRACT: 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 immunostimulatory metronomic Cytoxan (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 and elevated B- and T cells. Addition of an anti-PD-1 maintenance dose was necessary to overcome de novo PD-L1 intra-tumoral heterogeneity (ITH) associated recurrence in lung and liver mTNBC.

ORGANISM(S): Mus musculus

PROVIDER: GSE292908 | GEO | 2025/12/05

REPOSITORIES: GEO

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