Researchers Find a Way to Make Childhood Brain Tumors More Visible to the Immune System

Medulloblastoma, the most common malignant childhood brain cancer, can evade the immune system by limiting the expression of a protein that immune cells need to recognize cancer cells. Now, researchers at Columbia University Irving Medical Center (CUIMC) and the Herbert Irving Comprehensive Cancer Center (HICCC) have identified a way to overcome this defense in mouse models, pointing to a potential strategy for treating the disease. 

The study, published in Proceedings of the National Academy of Sciences (PNAS), found that increasing levels of a signaling protein called interferon gamma helped tumor cells express more of the surface protein MHC class I, making them more visible to T cells. Delivering interferon gamma directly into tumors prolonged survival in mice with medulloblastoma. 

Robert Wechsler-Reya, PhD, H. Houston Merritt Professor of Neurological Sciences at Columbia and a member of the HICCC, has studied medulloblastoma for years. Although modern treatments have improved outcomes, the disease remains difficult to treat, and survivors can experience lifelong side-effects from intensive therapy. 

“It’s a very aggressive disease that, if you didn’t treat it, would be deadly for every patient,” Wechsler-Reya says. With aggressive modern treatment, five-year survival rates are around 70 percent. “Which sounds promising, and of course, is better than the alternative. But, given how young the patients are when they are diagnosed, five-year survival is not a great benchmark.” 

Treatment-related effects can persist into adulthood, including cognitive deficits, endocrine disorders, and secondary cancers. Researchers are looking for ways to improve outcomes while addressing the limitations of existing therapies. 

Making Tumors Visible to T Cells

Many newer cancer treatments work by helping the immune system recognize and attack tumors. Medulloblastoma, however, has generally been considered an immunologically “cold” tumor, going unnoticed by the immune system. This keeps it out of reach of immunotherapies, which have revolutionized treatment for several other cancers. 

Wechsler-Reya and his collaborators investigated how medulloblastoma cells evade T cells, immune cells that can recognize and kill cancer cells. They found that the tumors express low levels of major histocompatibility complex class I (MHC class I), a protein that helps display cellular material for T cells to recognize. 

“The T cells can run around all they want, and they won’t see the tumor, and if they don’t see the tumor, they can’t kill it,” Wechsler-Reya says. 

Yet experiments in a mouse model revealed a more complicated relationship between the tumor and the immune system. When the researchers depleted killer T cells, the tumors grew more aggressively, suggesting that T cells were recognizing and helping control the cancer despite its low MHC class I expression. 

“The tumor lacks the molecule the T cells need to recognize it, so the question is, why does getting rid of the T cells make any difference?” Wechsler-Reya says. 

The researchers found that T cells can produce interferon gamma, a signaling protein that can stimulate tumor cells to increase MHC class I expression. This helps make the cancer cells more visible to the immune system. However, only some of the tumor cells turn on MHC class I. Those cells are effectively killed off by T cells, and the only tumor cells that remain are the ones that didn’t turn on MHC. Those cells evade immune attack. 

“It’s this self-limiting feedback loop where the T cells are effective, but only so much, and then the tumor cells outsmart the T cells by shutting off MHC class I and continuing to grow,” Wechsler-Reya says. It’s a lethal game of “Marco-Polo,” and some of the tumor cells cheat. 

Delivering Treatment Directly to the Tumor 

To determine whether boosting interferon gamma could overcome this immune-evasion mechanism, the researchers genetically modified tumor cells in their mouse model to produce more interferon. This increased tumor-cell killing and prolonged survival in the mice. 

Delivering interferon gamma as a treatment, however, presents two major challenges: Administering the protein intravenously can cause toxic side effects, and the blood-brain barrier limits how much of it can reach a brain tumor. 

The team therefore tested convection-enhanced delivery, a technique that delivers therapeutic agents directly into the brain through a catheter. By administering interferon gamma directly into medulloblastoma tumors, the researchers prolonged survival in mice. 

“We show that this works quite well, and we can prolong survival in mice by delivering interferon directly into the tumor,” Wechsler-Reya says. 

Next Steps Toward Treatment 

The findings suggest that using interferon to increase MHC class I expression could help make medulloblastoma more vulnerable to immune attack. Interferon may also enhance the effects of other immunotherapies when used in combination. However, the approach has so far been tested only in mice, and further research is needed to determine whether it could be developed into a treatment for children. Meanwhile, researchers at Columbia and elsewhere continue to evaluate and refine convection-enhanced delivery, a technique for delivering drugs directly to tumors. 

Wechsler-Reya plans to seek independent replication of the findings and discuss the feasibility of convection-enhanced delivery with clinicians. His laboratory is also investigating other ways to increase MHC class I expression in medulloblastoma, including potential drug-based approaches that would not require direct delivery into the tumor. 

These strategies could help researchers identify new ways to make medulloblastoma more susceptible to the immune system while addressing the challenges of delivering treatments to tumors in the brain.