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<p>Women 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 low-dose Cyclophosphamide (CTX) coupled with anti-CSF-1R antibody targeted therapy (SNDX-ms6352) and anti-PD-1 (ICB), was highly effective against aggressive metastatic <i>Trp53</i> null TNBC transplantable syngeneic models 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-5 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.</p>

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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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月3日

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  • Diego A. Pedroza,
  • Xueying Yuan,
  • Fengshuo Liu,
  • Hilda L. Chan,
  • Christina Zhang,
  • William Bowie,
  • Alex J. Smith,
  • Sebastian J. Calderon,
  • Nadia Lieu,
  • Weiguo Wu,
  • Paul Porter,
  • Poonam Sarkar,
  • Na Zhao,
  • Constanze V. Oehler,
  • Ondrej Peller,
  • M. Waleed Gaber,
  • Qian Zhu,
  • Charles M. Perou,
  • Xiang H-F. Zhang,
  • Jeffrey M. Rosen

摘要

Women 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 low-dose Cyclophosphamide (CTX) coupled with anti-CSF-1R antibody targeted therapy (SNDX-ms6352) and anti-PD-1 (ICB), was highly effective against aggressive metastatic Trp53 null TNBC transplantable syngeneic models 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-5 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.