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A recent study conducted by researchers at UCLA’s Jonsson Comprehensive Cancer Center has shed light on why certain brain tumors fail to respond to immunotherapy. The research provides valuable insights into the contrasting reactions of brain tumors that have spread from other parts of the body to the brain compared to glioblastoma, a highly aggressive brain cancer.
Immunotherapy, particularly through immune checkpoint blockade treatment, has shown promising results in activating both active and exhausted T cells in patients with tumors originating outside the brain but metastasizing to the brain. This indicates that the immune system is being stimulated to combat the cancer. However, the same response is not observed in patients with glioblastoma. This discrepancy arises because effective anti-tumor immune responses are primarily triggered in draining lymph nodes located outside the brain, a process that is not as efficient in cases of glioblastoma. Consequently, immunotherapy has been largely ineffective in treating glioblastoma, even though it has shown success in slowing or eradicating other types of cancer, such as melanoma, which often spreads to the brain.
This groundbreaking research, published in the Journal of Clinical Investigation, could have significant implications for improving the efficacy of immunotherapy for individuals with brain tumors and may suggest novel approaches to developing more effective therapies.
Dr. Robert Prins, the senior author of the study and a professor of molecular and medical pharmacology and neurosurgery at the David Geffen School of Medicine at UCLA, emphasized the importance of understanding the responsive tumor types and the underlying mechanisms to develop new therapies for traditionally non-responsive solid tumors like glioblastoma.
The researchers conducted their study by analyzing immune cells from nine individuals with metastatic brain tumors who had undergone immune checkpoint blockade treatment, comparing their findings to immune cells from 19 patients with brain metastases who had not received immunotherapy. They utilized a technique called single-cell RNA sequencing to examine the genetic material in both sets of samples and then compared this data to previously published analyses of 25 recurrent glioblastoma tumors, aiming to comprehend the impact of immunotherapy on T cells.
The results revealed distinct characteristics in the T cells of tumors that had spread to the brain, indicating a more efficient priming process occurring outside the brain, likely due to activation in lymph nodes. Before reaching the brain, T cells are initially activated in lymph nodes, where dendritic cells convey information about the tumor to T cells, enabling them to mount a better attack. Unfortunately, this priming process is not as effective when attempting to use immune checkpoint blockade for glioblastoma treatment.
Furthermore, the researchers identified a specific subgroup of exhausted T cells associated with extended overall survival in patients whose cancer had metastasized to the brain. Dr. Won Kim, a study author and surgical director of UCLA Health’s brain metastasis program, emphasized the significant difference observed in the response to immunotherapies between the two types of brain tumors. While there was a substantial increase in T cell lymphocytes within brain metastases following immunotherapy, the response in glioblastoma patients was not nearly as pronounced.
