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Tumor lineage-specific immune response in brain metastatic disease: opportunities for targeted immunotherapy regimen?
Shiva Najjary1, Johan M Kros1, Willem de Koning1
1Department of Pathology and Clinical Bioinformatics, The Tumor Immuno-Pathology Laboratory, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
Abstract:
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 a 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 fewer levels in some microglial cells in BM-LUAD. This is the first report on differences in the brain immune response between metastatic tumors 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.
Insights
Brain metastases from lung adenocarcinoma (BM-LUAD) show a more active immune response than breast cancer brain metastases (BCBM). BM-LUAD exhibits higher immune cell infiltration and expression of immune checkpoints like VISTA and IDO1, suggesting targeted immunotherapies.
Area of Science:
- Oncology
- Immunology
- Cancer Metastasis Research
Background:
- Brain metastases represent a severe complication of cancer with increasing incidence.
- Identifying specific druggable targets for brain metastases is a critical unmet need.
- Understanding the brain's immune response to different cancer types is crucial for developing effective treatments.
Purpose of the Study:
- To compare the brain immune response between lung adenocarcinoma brain metastases (BM-LUAD) and breast cancer brain metastases (BCBM).
- To identify distinct gene expression profiles and immune cell infiltration patterns in these two types of brain metastases.
- To evaluate potential immune targets for therapeutic intervention in brain metastases.
Main Methods:
- Targeted gene expression profiling of 11 BM-LUAD and 11 BCBM samples using NanoString nCounter PanCancer IO 360™ Panel.
- Spatial validation of key findings using GeoMx™ Digital Spatial Profiler (DSP) Technology.
- Immune cell profiling and drug target expression validation via multiplex immunohistochemistry.
Main Results:
- BM-LUAD exhibited a significantly more active immune response compared to BCBM, with 138 upregulated genes versus 28 in BCBM.
- Higher expression of CD45+, T cells, and cytotoxic T cell-related genes was observed in BM-LUAD.
- Spatial analysis revealed increased CD14 and CD163 expression in BM-LUAD, alongside higher expression of immune checkpoints VISTA and IDO1, primarily in tumor cells and immune cells.
Conclusions:
- This study is the first to report differences in the brain immune response between lung adenocarcinoma and breast cancer brain metastases.
- BM-LUAD demonstrates more extensive immune cell infiltration and higher expression of immune checkpoints (VISTA, IDO1) than BCBM.
- Targeted immunotherapies should be considered as a potential treatment strategy for patients with BM-LUAD.
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