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Updated: Sep 8, 2025
Digital Spatial Profiling for Characterization of the Microenvironment in Adult-Type Diffusely Infiltrating Glioma
Published on: September 13, 2022
Microenvironmental Landscape of Human Melanoma Brain Metastases in Response to Immune Checkpoint Inhibition
Christopher Alvarez-Breckenridge1,2, Samuel C Markson3,4,5,6, Jackson H Stocking7
1Departments of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Abstract:
Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. In addition, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM.
Insights
Researchers analyzed the tumor microenvironment of melanoma brain metastases to understand immune checkpoint inhibitor (ICI) effectiveness. They identified distinct immune cell states and T-cell interactions linked to treatment response, offering potential therapeutic targets.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Melanoma-derived brain metastases (MBM) present a significant clinical challenge with limited treatment options.
- Immune checkpoint inhibitors (ICI) show promise, but the MBM tumor microenvironment (TME) and its response to ICI are not fully understood.
Purpose of the Study:
- To characterize the MBM TME and identify factors associated with ICI response.
- To explore the relationship between intracranial and peripheral immune cell populations in MBM.
Main Methods:
- Single-cell RNA sequencing and T-cell receptor clonotyping were performed on 32 MBM samples and matched blood/extracranial lesions.
- Analysis focused on myeloid and T-cell phenotypes, clonotype distribution, and their correlation with clinical outcomes.
Main Results:
- Distinct neutrophil states, including IL8-expressing populations, were identified in the MBM TME, correlating with epithelial-to-mesenchymal transition.
- Significant associations were found between intracranial T-cell phenotypes, clonotype distribution, and ICI response.
- ICI-responsive MBM demonstrated interactions with peripheral blood similar to extracranial lesions.
Conclusions:
- The MBM TME exhibits unique features, including myeloid heterogeneity and specific T-cell infiltration patterns.
- Intracranial T-cell characteristics are linked to ICI efficacy, suggesting potential biomarkers and therapeutic targets.
- Understanding these MBM TME elements can guide strategies to improve patient outcomes with ICI therapy.
