NEW YORK – Using single-cell sequencing, a University of California at Los Angeles-led team has unearthed immune microenvironment patterns that may explain the distinct immune checkpoint blockade (ICB) immunotherapy responses described in individuals with metastatic brain cancer compared to recurrent glioblastoma (rGBM) patients.
"We hypothesized that ICB treatment is associated with divergent effects on the [tumor microenvironment] between the two types of brain tumors," senior author Robert Prins, a molecular, medical pharmacology, and neurosurgery researcher at the UCLA David Geffen School of Medicine and the Jonsson Cancer Center, and colleagues wrote in the Journal of Clinical Investigation on Friday.
They noted that findings from the current study "may help guide the development of new therapeutic strategies for improving ICB response in brain tumor patients."
For their analyses, researchers at the University of Zurich, UCLA, and UC San Francisco analyzed new and published data on nine ICB-treated brain metastases and 19 brain metastasis samples from individuals who had not yet been treated with immunotherapy. For the 17 samples not reported previously, they characterized immune clusters in the microenvironment using a combination of multiplex immunohistochemistry, cytometry by time-of-flight testing, and single-cell RNA sequencing.
From there, the team compared the microenvironment immune cell clusters in the metastatic brain tumors with those identified in a prior single-cell RNA-seq study on the microenvironment of recurrent glioblastoma, a tumor type that tends to have poorer immunotherapy responses.
"We really were trying to figure out which immune cells are changing in the more responsive tumors in order to better explain the higher response rate to the treatment," co-first author Lu Sun, a neurosurgery researcher at UCLA, said in a statement. "No study has comprehensively examined the differential effect of immune checkpoint blockade treatment on these two types of brain tumors before."
In particular, the team explained, past studies have shown that metastatic brain tumors may have immune checkpoint treatment responses that are similar to that of tumors found outside of the brain. In contrast, recurrent glioblastoma responses to checkpoint blockade immunotherapy are generally more muted than those reported for brain metastases originating elsewhere.
Together with the CyTOF, IHC data, and spatial transcriptomic data, the new and previously published scRNA-seq data profiles for more than 170,100 individual cells highlighted tumor-specific, post-treatment immune cell infiltration patterns that distinguished the metastatic brain tumor and rGBM samples, the researchers reported.
For example, T cell infiltration appeared to more pronounced in the metastatic brain tumors treated with ICB immunotherapy than in post-treatment rGBM samples. The microenvironment of tumors metastasizing to the brain also appeared to show an uptick in T cells with activated or exhausted T cell features relative to the rGBM samples, including a type of progenitor to exhausted T cells that seemed to track with enhanced overall survival in the patients with metastases to the brain.
In addition, the investigators described with a dip in macrophages expressing CD206 in a region known as the perivascular space in the brain metastases samples, potentially explaining the enhanced T cell access found in these brain tumors compared to tumors originating in the brain.
"We found quite a significant difference between the two types of brain tumors and how they respond to immunotherapies," co-author Won Kim, a UCLA neurosurgery and cancer researcher and surgical director of the UCLA Health brain metastasis program, said in a statement. "There was a tremendous number of T cell lymphocytes that were found within brain metastases following immunotherapy, and while the number of T cell lymphocytes also increased in glioblastoma patients, it wasn't anywhere near the same extent."