(R)-2-hydroxyglutarate drives immune quiescence in the tumor microenvironment of IDH-mutant gliomas

Diffuse low-grade and anaplastic gliomas (grades II and III, respectively) are infiltrative primary brain tumors that are considered malignant because of their invasiveness, resistance to therapy, and likelihood of transforming to higher grades. Median survival varies from 3 to 15 years as a proportion relentlessly progress, while others may remain stable for years (1). Molecular classification plays an integral role in the diagnosis and prognostication of patients with gliomas, as evidenced by the recently revised 2016 World Health Organization (WHO) Classification of Central Nervous System Tumors (2). One genetic marker that is of critical importance is the isocitrate dehydrogenase 1 (IDH) gene, which is found to be mutated in 80–90% of all WHO grades II and III gliomas and in a minority of grade IV tumors (glioblastoma, or GBM) (3). The most striking clinical feature of IDH-mutant (IDH-1 or IDH-2) gliomas, irrespective of tumor grade and histology, is their survival advantage when compared to IDH-wildtype gliomas. Although these tumors exhibit profound alterations to their genetic, metabolic and immunologic make up, it is still unclear what drives this survival advantage. Since its discovery, the R132H IDH mutation has changed the way that glial tumors are conceptualized and consequently treated, and it is well appreciated that the underlying biology and clinical behavior of these tumors are distinct and respond differently to current treatment paradigms (4)