Blocking fructose metabolism may improve brain tumor immunotherapy response

Northwestern Medicine scientists have discovered that specialized immune cells within the glioblastoma tumor metabolize fructose to suppress immune responses and promote tumor growth, reports a study published on March 17 in the Proceedings of the National Academy of Sciences.

The study, the first to identify this sugar pathway as a driver of immune suppression in brain tumors, suggests that blocking fructose metabolism in the specialized cells may improve immunotherapy response and patient outcomes.

"Across several mouse models, when we removed the fructose transporter, the tumors simply didn't grow," said study senior author Jason Miska, assistant professor of neurological surgery at Northwestern University Feinberg School of Medicine. "It was far more dramatic than we anticipated."

Glioblastoma is the most common and aggressive primary brain tumor in adults and has maintained a five-year survival rate of less than 7%, according to the National Brain Tumor Society.

It's one of the most treatment-resistant brain tumors in part because of its tumor microenvironment, the mix of cells surrounding the tumor. Those include immunosuppressive myeloid cells, which originate from the bone marrow, and brain-resident microglia, immune cells that normally protect the brain and central nervous system.

Microglia have been shown to be crucial for the early stages of tumor growth and maintain unique metabolic and immunologic processes in glioblastoma compared to infiltrating myeloid cells. Microglia also express a unique fructose transporter, GLUT5, that enables them to transport and metabolize fructose.

The role of microglial fructose metabolism in glioblastoma tumor progression, however, has remained poorly understood, according to Miska.

"We knew microglia use this fructose transporter as part of their normal biology, but we did not expect it to be this important for brain tumor growth," said Miska, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

"When we first saw these results nearly four years ago, it's what kept us going," he said. "The findings were so unexpected that we knew we had to keep digging deeper."

Discovering the fructose pathway

In mouse models of glioblastoma, the scientists used several laboratory techniques - including flow cytometry, which measures different types of cells, and genetic sequencing methods - to analyze microglia, macrophages (immune cells that can enter tumors from the bloodstream) and glioma tumor cells from the tumors and surrounding tissue.

This analysis not only confirmed that microglia uniquely express GLUT5 but also showed that microglia are the only immune cells in the glioblastoma microenvironment capable of metabolizing fructose.

The Northwestern scientists also studied tumors in mice genetically engineered without the GLUT5 transporter. These tumors showed a much stronger immune response, including better recognition of tumor cells, increased production of cytokines (signaling molecules that drive inflammation) and rapid multiplication of CD8+ T-cells, the immune system's main cancer-killing cells.

"This not only makes the microglia themselves more inflammatory, but it also causes those T-cells and B-cells that are in the tumor to be more activated and create more inflammatory molecules that we have shown are required for rejection of brain tumors," said Leah Billingham, a Northwestern postdoctoral fellow in Miska's laboratory and co-first author of the study.

"This isn't just solely the microglia doing something, this is an intricate interaction between the different parts of the immune system and how they are then impacting tumor rejection," Billingham said.

Improving cancer treatments

The findings suggest microglial fructose metabolism is a key regulator of immune suppression in glioblastoma and may be a promising therapeutic target to improve immunotherapy response in patients.

"The challenge with glioblastoma is that the standard of care has barely changed in 20 years," Miska said. "That's why identifying an entirely new therapeutic approach like this is so exciting."

Miska also noted the unique role of fructose in the brain compared to other organ systems: increased fructose consumption is associated with many inflammatory diseases, including colon cancer and diabetic neuropathy, but in the brain, fructose seems to instead suppress inflammation.

"Fructose consumption is associated with so many bad inflammatory outcomes in patients. What's interesting here is that in the brain, it seems to be working differently," Miska said. "It still helps the brain tumor grow, but now we're seeing something very different in the brain than we see in the rest of the body."

Going forward, Miska said his team aims to identify drugs designed to block cells from absorbing fructose that could then be tested in preclinical trials.

"Once we can get our hands on something that is promising as a fructose transport inhibitor, we will then take it into preclinical stages where we add standard-of-care therapies for brain tumors or immunotherapies and see if we can sensitize them," Miska said.