Evolution of the Tumor Microenvironment toward Immune-Suppressive Seclusion during Brain Metastasis of Breast Cancer: Implications for Targeted Therapy

SIMPLE SUMMARY: Brain metastases (BM) of breast cancer (BC) are new targets of immunotherapy, but their characteristics are unclear. Therefore, we analyzed the differential expression profile of the tumor microenvironment (TME) in primary breast cancer brain metastasis (BCBM). In the TME of BCBM, immune-related pathways were downregulated and tumor intrinsic factors were upregulated. Moreover, CD8+ T cells and M1 macrophages with cytotoxic effects were decreased, but M2 cells were increased, in BM. Most tumor-suppressive immune functions ceased after BM with a molecular subtype shift. These results suggest the need for targeted therapy and immunotherapy strategies for BCBM. ABSTRACT: Breast cancer (BC) is the second most common solid malignant tumor that metastasizes to the brain. Despite emerging therapies such as immunotherapy, whether the tumor microenvironment (TME) in breast cancer brain metastasis (BCBM) has potential as a target of new treatments is unclear. Expression profiling of 770 genes in 12 pairs of primary BC and matched brain metastasis (BM) samples was performed using the NanoString nCounter PanCancer IO360(TM) Panel. Immune cell profiles were validated by immunohistochemistry (IHC) in samples from 50 patients with BCBM. Pathway analysis revealed that immune-related pathways were downregulated. Immune cell profiling showed that CD8+ T cells and M1 macrophages were significantly decreased, and M2 macrophages were significantly increased, in BM compared to primary BC samples (p = 0.001, p = 0.021 and p = 0.007, respectively). CCL19 and CCL21, the top differentially expressed genes, were decreased significantly in BM compared to primary BC (p < 0.001, both). IHC showed that the CD8+ count was significantly lower (p = 0.027), and the CD163+ and CD206+ counts were higher, in BM than primary BC (p < 0.001, both). A low CD8+ T cell count, low CD86+ M1 macrophage count, and high M2/M1 macrophage ratio were related to unfavorable clinical outcomes. BC exhibits an immunosuppressive characteristic after metastasis to the brain. These findings will facilitate establishment of a treatment strategy for BCBM based on the TME of metastatic cancer.