Brain metastases are the most common tumor of the brain with a very poor prognosis. A fraction of patients with brain metastasis benefit from treatment with immune checkpoint inhibitors like anti-PD1, anti-PD-L1, and anti-CTLA4 drugs.
One of the limitations of these drugs over the long-term in brain tumors is that the cancers often recur, metastacizing with new lesions that don’t respond to immune-based therapies. Unfortunately, given the unique environment of brain cancers, and the difficulty in accessing ongoing samples of brain cancers, physicians are not currently able to monitor the evolution of these cells, and the level of immune cell infilatration, at a genomic level.
A new study from the Vall D’Hebron Institute of Oncology(VHIO) in Barcelona, Spain used personalized transcriptome sequencing to show that immune cells within the cerebrospinal fluid, particularly CD8 T-cells, faithfully model the characteristics of cells identified in brain metastasis, and could therefore constitute novel biomarkers of response to immune-based therapies.
Earlier research suggests that cerebrospinal fluid can act as a minimally invasive liquid biopsy – providing clues to the genetic characteristics of cells within and surrounding brain tumors. In this study, the VHIO team wanted to test whether they could effectively characterize the immunological phenotype of brain cancer cells through the analysis of cerebrospinal fluid.
The researchers analyzed samples from 48 patients with brain metastasis, performing single cell RNA transcriptome sequencing on 15,415 cells from brain metastases and matched cerebrospinal samples. Their goal was to see which immune cell types were present in both samples thereby providing an indication if cerebrospinal fluid contained sufficient information that recapitulated the tissue immunology.
They discovered a group of clonal T-cells in both metastasis and in cerebrospinal fluid that recognized the tumor and others that were active in immune-based therapy. Each immune T-cell had a unique sequence that recognized a particular tumor antigen. Using transcriptome sequencing they were able to characterize the individual sequences of immune cells, identify which immune cells are fighting the tumor, and observe how they evolve over time.
“We have analyzed the transcriptome of 50 brain metastases and observed that some of them bear and inflamed phenotype, being susceptible to respond to immune checkpoints blockers,” said Joan Seone, co-author and director of translational research at VHIO. The team found that the same T-cell clones were presents in the brain tumor and the CSF, confirming cell exchange between these two compartments.
“The analysis of the immune cells in the CSF using single-cell RNA sequencing and T-cell genotyping allows the characterization and monitoring of the brain metastasis immune landscape and can help predict the response of a fraction of patients with brain metastatic lesions to immune checkpoint blockers,” says Seone.
“By establishing similarities between the two, we have identified a novel and minimally invasive method that can allow us to predict response to immunotherapy in these patients; one that could more precisely guide clinical decision making in treating these patients with immune-based therapeutic strategies.”