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Updated: May 19, 2026
A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
Single-Cell Atlas of Renal Cell Carcinoma Brain Metastasis Uncovers Mechanisms of Immune Dysfunction and Resistance
Mostafa I H Ali1,2, Zeynep Feyza Akpinar1,2, Jose A Ovando-Ricardez1,2
1Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
Abstract:
Brain metastasis (BM) in renal cell carcinoma (RCC) remains poorly understood and often resistant to immune checkpoint inhibitors. We generated a large single-nucleus RNA-seq data of RCC BM, profiling 14 BM samples alongside matched extracranial metastases and primary tumors. Tumor cells in BM displayed neuronal infiltration, neural-like adaptation, and marked remodeling of the microenvironment, including expansion of immunosuppressive myeloid cells and depletion of antigen-presenting dendritic cells. Tumor, immune, and stromal cells exhibited metabolic rewiring characterized by fatty-acid metabolism, oxidative phosphorylation, and MYC-driven programs. CD8 T cells showed terminal exhaustion and impaired proliferative capacity, and tertiary lymphoid structures were absent. Spatial profiling of 12 BM samples (13,128 cells) validated key cellular interactions, while ligand-receptor analysis revealed immunoregulatory circuits between tumor, stromal, and immune cells. These findings define BM-specific adaptations that promote immune evasion and resistance, revealing therapeutic vulnerabilities in RCC BM.
Insights
Renal cell carcinoma (RCC) brain metastases show neural adaptations and immune evasion. These changes create resistance to therapies, highlighting new treatment targets for RCC brain tumors.
Area of Science:
- Oncology
- Neuroscience
- Immunology
Background:
- Brain metastasis (BM) in renal cell carcinoma (RCC) is poorly understood and often resistant to immune checkpoint inhibitors.
- Understanding the unique adaptations of RCC BM is crucial for developing effective treatments.
Purpose of the Study:
- To comprehensively characterize the cellular and molecular landscape of RCC brain metastases.
- To identify mechanisms of immune evasion and therapeutic resistance specific to RCC BM.
Main Methods:
- Single-nucleus RNA sequencing (snRNA-seq) of 14 RCC BM samples, matched extracranial metastases, and primary tumors.
- Spatial profiling of 12 BM samples to validate cellular interactions.
- Ligand-receptor interaction analysis to identify immunoregulatory circuits.
Main Results:
- RCC BM cells exhibit neuronal infiltration and neural-like adaptations.
- The tumor microenvironment is remodeled with expanded immunosuppressive myeloid cells and depleted dendritic cells.
- Tumor, immune, and stromal cells show metabolic rewiring (fatty-acid metabolism, oxidative phosphorylation, MYC programs).
- CD8+ T cells display terminal exhaustion, and tertiary lymphoid structures are absent.
- Spatial profiling confirmed key cellular interactions and identified immunoregulatory circuits.
Conclusions:
- RCC BM undergoes unique adaptations, including neuroglial remodeling and immunosuppressive niche formation.
- These adaptations contribute to immune evasion and therapeutic resistance in RCC BM.
- Identified vulnerabilities offer new avenues for site-specific therapeutic interventions in RCC BM.
