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Inhibition of Anti-Inflammatory Macrophage Phenotype Reduces Tumour Growth in Mouse Models of Brain Metastasis
Vasiliki Economopoulos1, Maria Pannell1, Vanessa A Johanssen1
1Department of Oncology, MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom.
Abstract:
Breast cancer brain metastasis is a significant clinical problem and carries a poor prognosis. Although it is well-established that macrophages are a primary component of the brain metastasis microenvironment, the role of blood-derived macrophages (BDM) and brain-resident microglia in the progression of brain metastases remains uncertain. The aim of this study, therefore, was to determine the role, specifically, of pro- and anti-inflammatory BDM and microglial phenotypes on metastasis progression. Initial in vitro studies demonstrated decreased migration of EO771 metastatic breast cancer cells in the presence of pro-inflammatory, but not anti-inflammatory, stimulated RAW 264.7 macrophages. In vivo, suppression of the anti-inflammatory BDM phenotype, specifically, via myeloid knock out of Krüppel-like Factor 4 (KLF4) significantly reduced EO771 tumour growth in the brains of C57BL/6 mice. Further, pharmacological inhibition of the anti-inflammatory BDM and/or microglial phenotypes, via either Colony Stimulating Factor 1 Receptor (CSF-1R) or STAT6 pathways, significantly decreased tumour burden in two different syngeneic mouse models of breast cancer brain metastasis. These findings suggest that switching BDM and microglia towards a more pro-inflammatory phenotype may be an effective therapeutic strategy in brain metastasis.
Insights
Targeting pro-inflammatory responses in blood-derived macrophages (BDM) and microglia may treat brain metastasis. Suppressing anti-inflammatory phenotypes significantly reduced breast cancer tumor growth in the brain.
Area of Science:
- Immunology
- Oncology
- Neuroscience
Background:
- Breast cancer brain metastasis is a major clinical challenge with poor outcomes.
- Macrophages, including blood-derived macrophages (BDM) and brain-resident microglia, are key components of the brain metastasis microenvironment.
- The specific roles of pro- and anti-inflammatory BDM and microglial phenotypes in metastasis progression are not fully understood.
Purpose of the Study:
- To investigate the impact of pro- and anti-inflammatory BDM and microglial phenotypes on breast cancer brain metastasis progression.
- To determine if modulating these phenotypes can serve as a therapeutic strategy.
Main Methods:
- In vitro co-culture assays using EO771 breast cancer cells and RAW 264.7 macrophages.
- In vivo studies in C57BL/6 mice using myeloid-specific knockout of Krüppel-like Factor 4 (KLF4).
- Pharmacological inhibition of Colony Stimulating Factor 1 Receptor (CSF-1R) and STAT6 pathways in syngeneic mouse models.
Main Results:
- Pro-inflammatory stimulated macrophages reduced breast cancer cell migration in vitro.
- Myeloid-specific knockout of KLF4, suppressing anti-inflammatory BDM, significantly reduced tumor growth in the brain.
- Pharmacological inhibition of anti-inflammatory BDM and/or microglial phenotypes decreased tumor burden in vivo.
Conclusions:
- Switching BDM and microglia towards a pro-inflammatory phenotype shows therapeutic potential.
- Targeting anti-inflammatory pathways involving KLF4, CSF-1R, or STAT6 may be a viable strategy for treating breast cancer brain metastasis.
