Mutations of the isocitrate dehydrogenase (IDH) protein help the cancerous version of a brain tumor known as a glioma evade therapies that involve revving up the immune system, a study indicates.
Another important finding was that inhibiting IDH mutations improved the effectiveness of an anti-glioma vaccine in mice.
The study, “Isocitrate Dehydrogenase Mutations Suppress STAT1 And CD8+ T Cell Accumulation In Gliomas,” was published in the Journal of Clinical Investigation.
Gliomas, which develop in the brain or spinal cord, are non-malignant to start with, and usually treatable. Lower-grade gliomas can become malignant and develop aggressive features, however — such as invasive growth, resistance to therapy, and increased risk of becoming higher-grade tumors, such as glioblastomas.
Mutations in the genes encoding IDH are among the genetic alterations that promote malignant glioma development.
“Among the earliest-signature molecular alterations, mutations in the isocitrate dehydrogenase IDH1 and IDH2 genes are of particular interest,” the researchers wrote. “These mutations have been found to be early and frequent (70%–80%) genetic alterations in [lower-grade glioma] patients, as well as in a small fraction of [glioblastomas] patients, especially those with secondary [glioblastomas] who progress from [lower-grade gliomas]. IDH mutations persist throughout multiple recurrences, chemotherapy, and resections.”
Researchers wanted to understand how the mutations help cancerous tumors survive.
They studied both human brain cells, or astrocytes, and mice with glioma. IDH mutations helped tumors evade immune system surveillance by activating molecular pathways that decrease the recruitment of T-cells. The researchers concluded that anticancer treatments based on revving up the immune system can fail because glioma cells are able to hide from the system.
IDH-C35, which inhibits the mutant IDH1 version of the IDH protein, improved the immune system’s capacity to detect cancer cells, they discovered. In glioma mouse models, this ability was enhanced when the animals were given a vaccine that helps activate the immune system.
“Our findings demonstrate what we believe to be a novel, IDH-[mutation]–mediated mechanism of immune evasion and further suggest that mutant IDH inhibitors can be used to enhance glioma immunotherapy in patients with IDH-[mutant] gliomas,” the team concluded.