Immune checkpoint blockade induces distinct alterations in the microenvironments of primary and metastatic brain...

Area of Science:

• Neuro-oncology
• Immunotherapy
• Translational Research

Background:

• Intracranial response of brain metastases (BrM) to immune checkpoint blockade (ICB) is less understood than recurrent glioblastoma (rGBM).
• Understanding BrM immune microenvironment is crucial for optimizing ICB efficacy.

Purpose of the Study:

• To compare the immune cellular landscape of BrM and rGBM in response to ICB.
• To identify mechanisms influencing T cell infiltration and patient survival in BrM treated with ICB.

Main Methods:

• Integrated single-cell RNA-Seq (scRNA-Seq) analysis of ICB-naive and ICB-treated BrM samples.
• Comparison with scRNA-Seq data from rGBM.
• Multiplex immunofluorescence and spatial transcriptomics to analyze macrophage populations and spatial architecture.

Main Results:

• ICB induced greater T cell infiltration into BrM compared to rGBM.
• BrM-infiltrating T cells showed tumor-specific, activated/exhausted phenotypes.
• ICB reduced CD206+ macrophages in the perivascular space, potentially facilitating T cell entry.
• A progenitor exhausted T cell subset correlated with improved overall survival in BrM patients.

Conclusions:

• ICB reshapes the immune microenvironment of BrM, enhancing T cell infiltration.
• Targeting specific macrophage populations may improve ICB effectiveness in brain tumors.
• Identification of prognostic T cell subsets offers potential therapeutic strategies for BrM.