Abstract
Brain metastases are the most common tumor of the brain with a dismal prognosis. A fraction of patients with brain metastasis benefit from treatment with immune checkpoint inhibitors (ICI) and the degree and phenotype of the immune cell infiltration has been used to predict response to ICI. However, the anatomical location of brain lesions limits access to tumor material to characterize the immune phenotype. Here, we characterize immune cells present in brain lesions and matched cerebrospinal fluid (CSF) using single-cell RNA sequencing combined with T cell receptor genotyping. Tumor immune infiltration and specifically CD8+ T cell infiltration can be discerned through the analysis of the CSF. Consistently, identical T cell receptor clonotypes are detected in brain lesions and CSF, confirming cell exchange between these compartments. The analysis of immune cells of the CSF can provide a non-invasive alternative to predict the response to ICI, as well as identify the T cell receptor clonotypes present in brain metastasis.
Highlights
Brain metastases are the most common tumor of the brain with a dismal prognosis
The detection of varying immune compositions and inflammation states could determine the response to immunotherapy and lays the ground for patient selection and stratification in the context of immune checkpoint inhibitors (ICI) therapies
Single-cell profiling allowed us to chart major cell types and transient tumor-specific states present in the Brain metastases (BrM) tumor microenvironment (TME)
Summary
Brain metastases are the most common tumor of the brain with a dismal prognosis. A fraction of patients with brain metastasis benefit from treatment with immune checkpoint inhibitors (ICI) and the degree and phenotype of the immune cell infiltration has been used to predict response to ICI. Instead of charting immune cell types from bulk transcriptome analysis (averaging of millions of cells) or using selected markers (flow or mass cytometry); in this work we have decided to use single-cell RNA sequencing (scRNA-seq). This approach provides the resolution required to draw a finegrained map of the immune TME, comprehensively phenotyping cell types, transient cell states and cancer-specific transcriptomes. The study is complemented with immunohistochemistry (IHC), flow cytometry (FC) and targeted gene expression analyses Major cell types, such as T cells, NK cells and tumor-associated macrophages (TAM)/microglia show highly variable frequencies and different phenotypic profiles across patients. TCR clonotypes in the CSF match those of the brain lesions, directly linking immune profiles from both compartments
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