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Anti-inflammatory Microglia/Macrophages As a Potential Therapeutic Target in Brain Metastasis
Kleopatra E Andreou1, Manuel Sarmiento Soto1, Danny Allen1
1Department of Oncology, Cancer Research UK and Medical Research Council, Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom.
Abstract:
Brain metastasis is a common complication of cancer patients and is associated with poor survival. Histological data from patients with brain metastases suggest that microglia are the major immune population activated around the metastatic foci. Microglia and macrophages have the ability to polarize to different phenotypes and to exert both tumorigenic and cytotoxic effects. However, the role of microglia/macrophages during the early stages of metastatic growth in the brain has not yet been determined. The aim of this study was to profile microglial/macrophage activation in a mouse model of breast cancer brain metastasis during the early stages of tumor growth, and to assess the role of the anti-inflammatory microglial/macrophage population, specifically, during this phase. Following intracerebral injection of 5 × 103 4T1-GFP mammary carcinoma cells into female BALB/c mice, robust microglial/macrophage activation around the 4T1 metastatic foci was evident throughout the time-course studied (28 days) and correlated positively with tumor volume (R2 = 0.67). Populations of classically (proinflammatory) and alternatively (anti-inflammatory) activated microglia/macrophages were identified immunohistochemically by expression of either induced nitric oxide synthase/cyclooxygenase 2 or mannose receptor 1/arginase 1, respectively. Temporally, levels of both pro- and anti-inflammatory cells were broadly stable across the time-course. Subsequently, selective depletion of the anti-inflammatory microglia/macrophage population by intracerebral injection of mannosylated clodronate liposomes significantly reduced metastatic tumor burden (p < 0.01). Moreover, increased levels of apoptosis were associated with tumors in clodronate liposome treated animals compared to controls (p < 0.05). These findings suggest that microglia/macrophages are important effectors of the inflammatory response in the early stages of brain metastasis, and that targeting the anti-inflammatory microglial/macrophage population may offer an effective new therapeutic avenue for patients with brain metastases.
Insights
Targeting anti-inflammatory microglia/macrophages significantly reduced breast cancer brain metastasis in mice. This suggests a new therapeutic strategy for brain metastases by modulating the immune response during early tumor growth.
Area of Science:
- Neuro-oncology
- Cancer immunology
- Tumor microenvironment
Background:
- Brain metastasis is a major cause of cancer-related mortality.
- Microglia and macrophages are key immune cells in the brain, with roles in both promoting and inhibiting tumor growth.
- The specific function of microglia/macrophages in early brain metastatic development remains unclear.
Purpose of the Study:
- To investigate microglial/macrophage activation during early breast cancer brain metastasis in a mouse model.
- To determine the role of the anti-inflammatory microglial/macrophage phenotype in this process.
- To evaluate the therapeutic potential of targeting anti-inflammatory microglia/macrophages.
Main Methods:
- Established a mouse model of breast cancer brain metastasis by intracerebral injection of 4T1-GFP cells.
- Quantified microglial/macrophage activation and tumor volume over 28 days.
- Immunohistochemically identified classically (pro-inflammatory) and alternatively (anti-inflammatory) activated microglia/macrophages.
- Depleted anti-inflammatory microglia/macrophages using clodronate liposomes and assessed tumor burden and apoptosis.
Main Results:
- Robust microglial/macrophage activation was observed around metastatic foci, correlating positively with tumor volume.
- Both pro-inflammatory and anti-inflammatory microglia/macrophages were present and stable throughout the study.
- Selective depletion of anti-inflammatory microglia/macrophages significantly reduced tumor burden and increased apoptosis.
- Targeting the anti-inflammatory phenotype showed a significant reduction in metastatic growth.
Conclusions:
- Microglia/macrophages play a critical role in the inflammatory response during early brain metastasis.
- The anti-inflammatory microglial/macrophage population supports early metastatic growth.
- Targeting anti-inflammatory microglia/macrophages represents a promising therapeutic strategy for brain metastases.
