Breast cancer brain metastasis is rapidly emerging as a critical problem in breast cancer. 15-30% of metastatic breast cancer patients develop brain metastasis, and studies project a >30% increase in patients as treatments for peripheral disease improve and patients live longer. This is alarming since there are no effective treatments and median survival is only a few months. There is growing interest in immunotherapeutic strategies to treat central nervous system (CNS) cancers, given that immune cells enter the brain while most conventional therapies are excluded by the blood brain barrier. Greater understanding of the immune response to brain metastasis will be needed to develop immunotherapy strategies effective in the unique immune microenvironment of the CNS.
The brain immune microenvironment is principally composed of specialized tissue resident macrophages called microglia that tile the brain and play diverse functions in CNS homeostasis and disease. Microglia represent an attractive immunotherapeutic target because they are the first line of defense to disease in the CNS. Brain metastases are heavily infiltrated with tumor associated macrophages (TAMs), which may be comprised of microglia, border associated macrophages, and bone marrow derived monocytes and macrophages. Previous work has indicated a tumor promoting role for TAMs, but it is unclear whether microglia or other TAMs produce these tumor promoting effects.
Microglia promote anti-tumor immunity and suppress breast cancer brain metastasis
Breast cancer brain metastasis (BCBM) is a lethal disease with no effective treatments. Prior work has shown that brain cancers and metastases are densely infiltrated with anti-inflammatory, protumorigenic tumor associated macrophages (TAMs), but the role of brain resident microglia remains controversial because they are challenging to discriminate from other TAMs. Using single-cell RNA-sequencing (scRNA-seq), genetic, and humanized mouse models, we specifically identify microglia and find that they play a distinct pro-inflammatory and tumor suppressive role in BCBM. Animals lacking microglia show increased metastasis, decreased survival, and reduced NK and T cell responses, showing that microglia are critical to promote antitumor immunity to suppress BCBM. We find that the pro-inflammatory response is conserved in human microglia, and markers of their response are associated with better prognosis in BCBM patients. These findings establish an important role for microglia in anti-tumor immunity and highlight them as a potential immunotherapy target for brain metastasis.
UMAPs (Evans, Blake, Longworth et al, 2023)
tSNE plot of mouse cells from control and metastatic brains (n=42,891).
tSNE plot of myeloid cells (n=24,348) from control (blue) and metastatic (red) brains.
UMAP of CD45+ immune cells (n=31,053 cells) in control and metastatic brains sorted by flow cytometry.
UMAP of microglia from control and metastatic brains. Cells were downsampled to display an equal number of microglia from each condition (n=1000 cells per condition).
UMAP of T cells (n=1949 cells) from metastatic brains at day 4 and 10 post cancer cell injection.
tSNE plot shows iHPSC-derived human myeloid cells (n=21,353) from control (blue) and metastatic (red) brains.