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Cancer

Distinct Gene Expression Programs in Brain Metastases: Insights into Immunotherapy Resistance

Strategic Insights

— 1 min read

Researchers applied single-nucleus RNA sequencing and spatial transcriptomics to identify potential therapeutic targets in brain metastases from patients with renal cell carcinoma. The study found that brain metastases had distinct gene expression programs, lower antitumor immune cell infiltration, and unique interactions with the brain microenvironment. These findings suggest that brain metastases may be resistant to immunotherapy, and that new treatments are needed to address this issue.

Key Takeaways:

  • Brain metastases from patients with renal cell carcinoma have distinct gene expression programs compared to primary tumors or metastases in other organs.
  • The tumor microenvironment of brain metastases has lower antitumor immune cell infiltration, including T cells, memory B cells, dendritic cells, and monocytes.
  • Neuronal and glial cells in the brain interact with tumor cells and immune cells, potentially suppressing antitumor immune activity.
  • Macrophages in the brain express an immune-suppressing M2 gene signature and have higher levels of serum amyloid A1.
  • Tumor cells in the brain have increased expression of genes involved in mTORC1 signaling, epithelial-mesenchymal transition, fatty acid metabolism, oxidative phosphorylation, and response to reactive oxygen species.
  • The study highlights the power of single-nucleus RNA sequencing and spatial transcriptomics to uncover facets of disease biology.
  • The findings have the potential to serve as biomarkers or therapeutic targets for patients with renal cell carcinoma that has metastasized to the brain.

Statistics:

  • Over 25 percent of patients with renal cell carcinoma treated with immune checkpoint inhibition may develop brain metastases.
  • The study analyzed 14 brain metastases, 8 matched primary kidney tumors, and 5 matched extracranial metastases via single-nucleus RNA sequencing.
  • The spatial transcriptomics analysis included 57 brain metastases.
  • Tumor cells in the brain metastases had higher activity of the VEGFR and FGFR4 growth-promoting proteins.
  • Macrophages in the brain had a higher expression of serum amyloid A1.

Sources:

  • American Association for Cancer Research, "RESEARCHERS APPLIED SINGLE-NUCLEUS RNA SEQUENCING AND SPATIAL TRANSCRIPTOMICS TO IDENTIFY POTENTIAL THERAPEUTIC TARGETS IN BRAIN METASTASES"
  • Institute/Research Center: The University of Texas MD Anderson Cancer Center
  • Funding sources:

+ Kidney Cancer Association Young Investigator Award 2021

+ International Kidney Cancer Coalition Cecile and Ken Youner Scholarship 2021

+ Society of Immunotherapy of Cancer-Nanostring Single Cell Biology Award 2022

+ Cancer Prevention and Research Institute of Texas (RP180684)

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