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Microglia coordinate the anti-tumor immune response to breast cancer brain metastasis [Foxn1 nu/nu 10X data]

ABSTRACT: We used single-cell RNA-sequencing to investigate the role of brain-resident microglia versus infiltrating cells in a mouse model of breast cancer brain metastasis (BCBM). We generated brain metastases with a cardiac-injection of the human triple-negative breast cancer cell line MDA-MB-231BR2 (231BR) into Foxn1 nu/nu mice and allowed tumors to grow in the brain for four weeks. We then compared astrocytes (ASCA2+CD45-) and myeloid cells (CD11b+CD45+) from these mice verses control Foxn1 nu/nu brains to find transcriptional changes associated with BCBM.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE147942 | GEO | 2023/09/01

REPOSITORIES: GEO

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Project description:Metastases in the brain are the most severe and devastating complication of cancer. The incidence of brain metastasis is increasing. Therefore, the need of finding specific druggable targets for brain metastasis is demanding. The aim of this study was to compare the brain (immune) response to brain metastases of the most common tumor lineages, viz., lung adenocarcinoma and breast cancer. Targeted gene expression profiles of 11 brain metastasis of lung adenocarcinoma (BM-LUAD) were compared to 11 brain metastasis of breast cancer (BCBM) using NanoString nCounter PanCancer IO 360™ Panel. The most promising results were validated spatially using the novel GeoMx™ Digital Spatial Profiler (DSP) Technology. Additionally, Immune cell profiles and expression of drug targets were validated by multiplex immunohistochemistry. We found more active immune response in BM-LUAD as compared to BCBM. In the BM-LUAD, 138 genes were upregulated as compared to BCBM (adj. p ≤ 0.05). Conversely, in BCBM 28 genes were upregulated (adj. p ≤ 0.05). Additionally, genes related to CD45+ cells, T cells and cytotoxic T cells showed to be expressed higher in BM-LUAD compared to BCBM (adj. p = 0.01, adj. p = 0.023, adj. p = 0.023, respectively). The spatial quantification of the immune cells using the GeoMx DSP technique revealed the significantly higher quantification of CD14 and CD163 in tumor regions of BM-LUAD as compared to BCBM. Importantly, the immune checkpoint VISTA and IDO1 were identified as highly expressed in the BM-LUAD. Multiplex immunohistochemistry confirmed the finding and showed that VISTA is expressed mainly in BM-LUAD tumor cells, CD3+ cells, and to less levels in some microglial cells in BM-LUAD. This is the first report on differences in the brain immune response between metastatic tumor of different lineages. We found a far more extensive infiltration of immune cells in BM-LUAD as compared to BCBM. In addition, we found higher expression of VISTA and IDO1 in BM-LUAD. Taken together, targeted immune therapy should be considered to treat patients with BM-LUAD.

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Microglia coordinate the anti-tumor immune response to breast cancer brain metastasis [Foxn1 nu/nu 10X data]

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