Biology subjects

Gerstner, E. R.

Publications and source records attributed to Gerstner, E. R..

3 recordsLinked to original sources

bioRxiv2023

Structural and functional vascular dysfunction within brain metastases is linked to pembrolizumab inefficacy

Structurally and functionally aberrant vasculature is a hallmark of tumor angiogenesis and treatment resistance. Given the synergistic link between aberrant tumor vasculature and immunosuppression, we analyzed perfusion MRI for 44 patients with brain metastases (BM) undergoing treatment with pembrolizumab. To date, vascular-immune communication, or the relationship between immune checkpoint inhibitor (ICI) efficacy and vascular architecture, has not been well-characterized in human imaging studies. We found that ICI-responsive BM possessed a structurally balanced vascular makeup, which was linked to improved vascular efficiency and an immune-stimulatory microenvironment. In contrast, ICI-resistant BM were characterized by a lack of immune cell infiltration and a highly aberrant vasculature dominated by large-caliber vessels. Peri-tumor region analysis revealed early functional changes predictive of ICI resistance before radiographic evidence on conventional MRI. This study was one of the largest functional imaging studies for BM and establishes a foundation for functional studies that illuminate the mechanisms linking patterns of vascular architecture with immunosuppression, as targeting these aspects of cancer biology may serve as the basis for future combination treatments.

cancer biology↗

bioRxiv2021

Microenvironmental correlates of immune checkpoint inhibitor response in human melanoma brain metastases revealed by T cell receptor and single-cell RNA sequencing

Melanoma-derived brain metastases (MBM) represent an unmet clinical need due to central nervous system (CNS) progression as a frequent, end-stage site of disease. Immune checkpoint inhibition (ICI) represents a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique MBM-TME elements and correlates of MBM-ICI response, 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, most notably multiple distinct neutrophil states including an IL-8 expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. Additionally, we observe 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 demonstrate unique features of the MBM-TME, which may represent potential targets to improve clinical outcomes for patients with MBM.

cancer biology↗

bioRxiv2019

Altered structural hub connectivity and its clinical relevance in glioma

Background and PurposeStructural network analysis of diffusion imaging is increasingly used to study neurological disease, its pathophysiology and symptoms. We therefore evaluate structural hub connectivity in glioma patients and its association with molecular subtype and clinical status.\n\nMaterials and MethodsUsing retrospective diffusion imaging, structural connectivity was investigated in 65 newly diagnosed glioma patients (36 males; mean age 52 {+/-} 14 years) and 60 healthy controls (23 males; mean age 50 {+/-} 7 years). Probabilistic tractography was performed between 39 cortical nodes per hemisphere. In patients, tumors were drawn in to exclude each tumor-containing voxel from analysis. As previous connectomic research in glioma and other neurological diseases has shown particular importance of hub nodes and connections, the numbers of connections between hubs, hubs and non-hubs, and non-hubs were calculated for each hemisphere separately. Clinical and molecular characteristics were assessed as part of routine clinical care. Group differences in connectivity and its associations with performance and molecular subtypes were tested non-parametrically through Mann-Whitney U-tests, corrected for multiple comparisons.\n\nResultsGlioma patients had more hub-related connections in the hemisphere contralateral to the tumor (hub-hub P = 0.002, hub-non-hub P = 0.005), despite being comparable to controls in terms of total and ipsilateral connections. Within patients, hub-related connectivity related to performance status (P = 0.009) and molecular subtype (P = 0.045).\n\nConclusionWe present experimental evidence for the relevance of structural connectomics as a tool to pick up on the clinical impact of glioma on the rest of the brain.

cancer biology↗