Northwestern Medicine scientists have discovered that specialised immune cells within the glioblastoma tumour metabolise fructose to suppress immune responses and promote tumour growth, reports a study published 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 tumours, suggests that blocking fructose metabolism in the specialised cells may improve immunotherapy response and patient outcomes.

“Across several mouse models, when we removed the fructose transporter, the tumours 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 tumour in adults and has maintained a five-year survival rate of less than 7%, according to the National Brain Tumour Society.

It’s one of the most treatment-resistant brain tumours in part because of its tumour microenvironment, the mix of cells surrounding the tumour.

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 tumour 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 metabolise fructose.

The role of microglial fructose metabolism in glioblastoma tumour 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 tumour growth,” said Miska, who is also a member of the Robert H. Lurie Comprehensive Cancer Centre 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 analyse microglia, macrophages (immune cells that can enter tumours from the bloodstream) and glioma tumour cells from the tumours 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 metabolising fructose.

The Northwestern scientists also studied tumours in mice genetically engineered without the GLUT5 transporter.

These tumours showed a much stronger immune response, including better recognition of tumour cells, increased production of cytokines (signalling 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 tumour to be more activated and create more inflammatory molecules that we have shown are required for rejection of brain tumours,” 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 tumour 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 tumour 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 tumours or immunotherapies and see if we can sensitise them,” Miska said.

Article: Microglial fructose metabolism is essential for glioblastoma growth

Source: Northwestern University