Glioblastoma brain cancer, CT scan

New evidence suggests lymph nodes play a key role in why tumors that have spread to the brain respond to immunotherapy, while glioblastoma, which originates in the brain, does not.

“Typically, antigen presenting cells (e.g., conventional dendritic cells, cDCs) are recruited to the tumor, where they phagocytose dead or dying tumor cells,” senior author Robert Prins tells Inside Precision Medicine. Prins is a professor of molecular and medical pharmacology and of neurosurgery at the David Geffen School of Medicine at UCLA.

He further explains that receptors on the dead cells activate the cDC and these cells then migrate to the nearest lymph node and prime naïve T cells moving through there. This circuit does not work very well in primary brain tumors, such as glioblastoma. “No one is really certain why,” he adds.

“We found quite a significant difference between the two types of brain tumors and how they respond to immunotherapies,” says co-author Won Kim, surgical director of UCLA Health’s brain metastasis program. “There was a tremendous number of T cell lymphocytes 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.”

The research, published in the Journal of Clinical Investigation, could lead to improvements in immunotherapy for people with brain tumors.

While it is not effective in treating glioblastoma, immunotherapy can slow or even eradicate other types of cancer, such as melanoma, which frequently metastasizes to the brain. The world market for immunotherapies is estimated to be worth over $100 billion, but these drugs only work in about 20% of patients.  The incidence of glioblastoma ranges from 0.59 to 5 per 100,000 persons, and it is on the rise in many countries.

Prins says the team’s findings, “Suggest that enhancing the activation and presentation of T cells by dendritic cells could be a potential treatment strategy.”

In people with tumors that originated in other parts of the body but spread to the brain, immune checkpoint blockade appears to elicit a significant increase in both active and exhausted T cells—signs that the T cells have been triggered to fight the cancer. In people with glioblastoma that process is not very effective.

These researchers studied immune cells from nine people with metastatic brain tumors who had been treated with immune checkpoint blockade and compared these cells with immune cells taken from 19 patients with brain metastases, but not treated with immunotherapy.

The team used single-cell RNA sequencing to examine both sets of samples, and then compared the data to previously published analyses of 25 recurrent glioblastoma tumors to better understand the effect the immunotherapy had on T cells.

“We were able to study the transcriptional profile of individual immune cells, to see how this changed following immunotherapy, and finally to compare these profiles between metastatic brain tumors and glioblastoma,” says Prins.

“We 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,” notes study co-lead author, Lu Sun, a project scientist in the Geffen School of Medicine’s neurosurgery department. “No study has comprehensively examined the differential effect of immune checkpoint blockade treatment on these two types of brain tumors before.”

In future studies, the researchers plan to analyze data from a larger, more uniform group of people who were diagnosed with melanoma that had spread to the brain.

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