A type of aggressive, treatment-resistant brain tumour has a distinct population of immune cells that support its growth, according to new research led by investigators at the Johns Hopkins Kimmel Cancer Centre Bloomberg~Kimmel Institute for Cancer Immunotherapy and the Johns Hopkins University School of Medicine.

Searching for subtypes of immune cells seen only in the most serious, grade 4 brain tumours, called glioblastomas, and using a recently developed technology called spatial genomics, the researchers found that glioblastoma stem cells were co-localised with a type of immunosuppressive cell called myeloid-derived suppressor cell (MDSC), and that these two cells symbiotically feed off of each other to promote tumour growth and aggressiveness.

A description of the work was published in the journal Science.

“Tumour stem cells represent only 5% to 10% of the tumour, but they’re the critical cells that are renewing and generating the rest of the tumour and are essentially responsible for the aggressiveness of the tumour,” says senior study author Drew Pardoll, M.D., Ph.D., the Martin D.

Abeloff Professor of Cancer Research , co-director of the Mark Foundation Centre for Advanced Genomics and Imaging, and director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy.

“We found that the myeloid-derived suppressor cells and tumour stem cells literally were in the same place — a region described by pathologists in the 1980s as the pseudopalisading region. There was a very intimate connection.”

To better characterise the cellular components of brain cancer, investigators performed single-cell RNA sequencing on tissue samples from 33 types of brain tumours spanning from low to high grade, finding two populations of MDSCs in IDH-WT glioblastoma.

Then, using a technique called spatial transcriptomics to look at patterns of gene expression of over 750,000 immune cells and more than 350,000 tumour and associated cells in these samples, they found MDSCs were co-located with the tumour stem cells.

“Glioblastoma is a highly aggressive brain tumour with remarkable ability to evade the immune system, which has made immune-based therapies largely ineffective to this point,” said first and co-corresponding author, Christina Jackson, M.D.

, an assistant professor of neurosurgery at the Perelman School of Medicine at the University of Pennsylvania, who was at Johns Hopkins at the time the research was conducted.

“Our study revealed a distinct subset of immune cells, known as myeloid-derived suppressor cells that promote glioblastoma growth, providing new insights into how the tumour interacts with the immune system. By identifying these cells and their role, we hope to uncover new therapeutic targets andlay the groundwork for more effective treatments.”

In their studies, investigators discovered that the two types of cells were feeding each other in the brain tumours.

Tumour stem cells were producing chemical signals called chemokines that attracted the MDSCs, and making growth factors and activation factors for the MDSCs.

In turn, the MDSCs were producing growth factors for the tumour cells.

The researchers were able to further ascertain what specific molecules tumour stem cells were producing to attract and activate MDSCs.

Two of the key ones identified by the team were IL (interleukin)-6 and IL-8, which play a role in inflammatory responses, and for which MDSCs have receptors.

“IL-8 is one of the major attractants to bring the MDSCs to the tumour, and IL-6 is one of the major activators of the MDSCs,” Pardoll says.

On the flip side, the team found that MDSCs secreted a growth factor called fibroblast growth factor 11 (FGF11) to feed the stem cells, a molecule never before known to be involved in brain or other cancers.

Along the way, Jackson, Pardoll and colleagues found that tumours with a mutation in the IDH1 gene, which are less aggressive, had almost no MDSCs and far fewer cancer stem cells.

This led them to look across all brain cancers at the correlation between MDSC infiltration and survival.

Using the National Cancer Institute’s Cancer Genome Atlas (TCGA) database of cancer samples, they indeed found that very tight correlation — the fewer cancer stem cells and fewer MDSCs a person had in their tumours, the better they did.

While additional studies are needed to further understand these cellular interactions, the work is exciting in that it suggests additional potential targets to block in treatment of these aggressive brain tumours, Pardoll says.

For example, Jamie Spangler, Ph.D., an associate professor of biomedical engineering at Johns Hopkins, has developed an investigational bispecific antibody that binds to the receptors for IL-6 and IL-8, blocking their signalling.

Source: Johns Hopkins Medicine