Tumours of the brain and spinal cord, or gliomas, are among the most commonly occurring brain tumours.

Although a majority of gliomas are classified as curable, these low-grade tumours have the potential to develop more aggressive traits and become resistant to tumour-targeting approaches, including immunotherapy.

In a study published this week in the JCI, Hideho Okada's lab at UCSF investigated whether acquired mutations in the enzyme isocitrate dehydrogenase (IDH), which are common in low-grade gliomas, help these tumours become resistant to immunotherapy.

In an accompanying commentary, also available through the JCI, Dr David Hafler notes that "Understanding how to increase immune infiltration of gliomas represents a key first step in achieving tumor destruction through immunotherapy."

In both human astrocytes and mouse models of glioma, the IDH mutations impaired immune responses in the tumour environment by reducing the recruitment of T cells.

Thus, the IDH mutations may help gliomas avoid anti-tumour targeting by therapies that rely on immune system activation.

Importantly, inhibition of the mutant IDH enzyme enhanced the efficacy of a vaccine-based immunotherapy treatment in glioma-bearing mice.

This finding suggests that combinatorial therapies may be able to counteract the effects of the IDH mutation to improve clinical responses to immunotherapy treatments for glioma.

"We report for the first time to our knowledge that IDH mutations in glioma cells lead to decreased STAT1 protein levels, which regulate T cell–attracting chemokines and impact CD8 T cell accumulation" the authors write in the main paper. "Strategies to improve CD8 T cell accumulation in the tumour, such as the use of mutant IDH inhibitors, should be considered for integration into T cell–based therapies for patients with IDH-MUT gliomas."

Source: JCI