Glioblastoma Study Improves Understanding of How Immune Cells Function in the BrainApril 4, 2023 - Eden McCleskey
What can glioblastoma (GBM) tumors teach us about diseases like ALS, Alzheimer's, Parkinson's and MS? Can a better understanding of the diversity and activation states of immune cells in gliomas unlock secrets about how other diseases of the brain work?
One person uniquely well qualified to answer these questions is Houston Methodist researcher Kyuson Yun, Ph.D., whose recent landmark study in Nature Communications analyzed more than 200,000 distinct cell types associated with deadly GBM tumors and provided the first comprehensive picture of how immune cells interact with cancer cells to help cancer cells grow.
As such, the study produced a first-of-its-kind database, a veritable "who's who" list of cancer and immune cells (microglia, macrophages, T cells and myeloid-derived suppressor cells). It also clearly demonstrates different types of immune cells that promote or suppress immune responses, explores how different cells talk to each other and sheds insight on why many immunotherapies have failed to treat gliomas.
The study represents one of the most significant contributions to brain research in recent years.
To provide additional context about her research and its implications for neuro-oncology, Dr. Yun has been selected to deliver a presentation at the prestigious American Association of Neurology (AAN) Annual Meeting on April 24, 2023.
Leading Medicine recently sat down with the star investigator to get a sneak peek at the topics she'll be discussing at AAN and catch up on the latest research keeping her lab busy and in high demand.
Q: Tell us about your single-cell analysis of glioblastoma study. What is unique about it?
Dr. Yun: We wanted to get a complete picture of all the types of cells that are present in the glioma microenvironment and how they interact with other cells to help promote disease progression. To study the extensive spatial and molecular heterogeneity of GBM, we collected samples from 18 patients and from three to five locations within each patient's tumor. We isolated individual cells and sequenced and analyzed them from each sample separately, resulting in the extremely robust dataset of more than 200,000 cells. It required a significant investment of time, expertise and capital and could only be performed at a large academic medical center like Houston Methodist with both high-volume clinical expertise in glioblastoma and the research infrastructure to support a single-cell study of this scope. We did the legwork and then published it in an accessible format so anybody can go in and use the data to advance their own studies.
Q: What were the big takeaways?
Dr. Yun: We learned a lot about the different flavors of immune cells that can promote or suppress glioma growth. Our analysis identified nine molecularly distinct myeloid subtypes: four microglia, four bone marrow-derived macrophage and dendritic cell subtypes.
We found that high levels of microglia — the brain's resident immune cells — were associated with better survival. High levels of the other five subtypes — recruited from the blood and bone marrow to come to the brain to fight the disease — were associated with poor survival. We're still investigating why, but it was a big discovery to see this clear delineation between brain resident immune cells being good and bone marrow-derived immune cells being bad.
The study's other really important discovery is that a protein called S100A4 is a very promising immunotherapy target. S100A4 is most preferentially expressed in bad myeloid cells and T cells that allow cancer cells to evade immune surveillance. We found that high levels of S100A4 are required for immune-suppressive macrophages and Tregs to block T cell infiltration and dendritic cell maturation.
In our GBM mouse models, when you genetically delete S100A4 either from the cancer cells or the host cells, more T cells can come in and fight the cancer. The animals live much longer in the presence of this activated immune system.
Q: What is the connection to other kinds of neurological disease?
Dr. Yun: So, in GBM, the problem is the immune cells are suppressed, and they aren't attacking the threat. In diseases like Alzheimer's, ALS, Parkinson's, etc., the problem is the opposite. For some reason, the immune cells are overly active and need to be turned off. Being able to turn up or turn down the immune response would help both patient populations.
Neuroinflammation is an emerging and very important new direction for studying and understanding diseases in the brain. For the past century, researchers were focused on the neurons that were dying in neurodegenerative diseases. The new thinking is that neurodegenerative diseases may have immune components that are initiating the disease process years before the neurons start dying.
For example, the gene most associated with Alzheimer's is expressed in microglia. In GBM, microglia expression of this gene is good. But in Alzheimer's it is bad. That's another indicator that we're looking at flip sides of the same coin.
Our work in GBM dovetails nicely with research on neurodegenerative disease. We're trying to understand how the immune cells get hyper-activated in neurodegenerative disease so we can use the same mechanism to turn the immune system on in cancer. And vice versa for researchers trying to prevent or treat neurodegenerative disease. If we wind up make progress in each other's lanes, so much the better.
Q: What are the next steps in your research?
Dr. Yun: We're doing multiple follow-up studies on S100A4 and trying to develop it into an effective therapy. We believe it could be used as a new immunotherapy target — a drug that makes other cancer treatments more effective by turning off the signal that tells the immune system not to fight.
There is an FDA-approved antipsychotic drug that seems to abolish S100A4 in mouse brain tumors. We're looking into doing a Phase Zero clinical trial on this drug to see if it has the desired immunomodulatory effect in glioma patients.
We are also developing a brand-new therapeutic antibody against S100A4. It is important for cancer metastasis, and we have an S100A4 antibody that can block breast cancer metastasis to the lung. We are currently making this antibody into a drug for treating breast and other cancer metastases. For treating glioblastoma, we are currently doing studies on engineering it to more easily cross the blood-brain barrier.
We have a study about selectively targeting immune-suppressive immune cells that basically picks up where our original study left off. We showed that some immune cells are good, and some are bad, which means you can't go in blindly and try to reprogram or remove all myeloid cells. It has to be done in a cell-type specific manner. We found that S100A4 has the selective ability to target immune suppressive cells and bone-marrow derived immune cells while sparing the good immune cells. We have several other candidate molecules we are studying now. We are also adding a new layer of information to our earlier study to understand the geographic context in which these interactions occur. We are performing "spatial sequencing," which will allow us to map all the different cell types in the glioblastoma tissues so that we can understand the composition of neighborhoods in which different cell types talk to each other.
We're also expanding our neuroinflammation phenotype research to understand other diseases in the brain and the role of immune-promoting and immune-suppressive cells in these disease states.
In summary, we're still trying to get a better understanding of how the brain, cancer and the immune system interact.