Immune cell profiling of the cerebrospinal fluid enables the characterization of the brain metastasis microenvironment

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.

Multidiscipline Immunotherapy-Based Rational Combinations for Robust and Durable Efficacy in Brain Metastases from Renal Cell Carcinoma

“…A fraction of patients with BM benefit from treatment with ICI [214][215][216], and the degree and phenotype of immune cell infiltration have been used to predict the response to ICI [214]. The divergent results of immunotherapy in patients with BM allow for the data-driven design of novel therapeutic interventions [42,217,218].…”

“…The divergent results of immunotherapy in patients with BM allow for the data-driven design of novel therapeutic interventions [42,217,218]. CSF can provide fundamental information about the genomic characteristics of BM and hence can be used as a relatively non-invasive liquid biopsy [214,219,220]. A continuum of cellular T cell states indicates tumor reactivity and clonal expansion, which are also detectable in the CSF [214].…”

“…CSF can provide fundamental information about the genomic characteristics of BM and hence can be used as a relatively non-invasive liquid biopsy [214,219,220]. A continuum of cellular T cell states indicates tumor reactivity and clonal expansion, which are also detectable in the CSF [214]. Importantly, inflammatory states that can predict ICI response, such as CD8+ T cell tumor infiltration, are recapitulated in CSF analysis [214].…”

“…A continuum of cellular T cell states indicates tumor reactivity and clonal expansion, which are also detectable in the CSF [214]. Importantly, inflammatory states that can predict ICI response, such as CD8+ T cell tumor infiltration, are recapitulated in CSF analysis [214]. CSF can recapitulate the immune landscape of the brain lesion, indicating that analysis of the CSF can provide critical information about the brain TME in a relatively non-invasive manner, as well as characterize and assess the degree of inflammation in brain lesions, which could be used to predict the response to ICIs [214].…”

“…Importantly, inflammatory states that can predict ICI response, such as CD8+ T cell tumor infiltration, are recapitulated in CSF analysis [214]. CSF can recapitulate the immune landscape of the brain lesion, indicating that analysis of the CSF can provide critical information about the brain TME in a relatively non-invasive manner, as well as characterize and assess the degree of inflammation in brain lesions, which could be used to predict the response to ICIs [214]. Importantly, TCR clonotypes in the CSF match those of brain lesions, directly linking immune profiles from both compartments [214].…”