Immu-19. mutant isocitrate dehydrogenase 1 in glioma causes a reduction in adenosinergic pathway signaling within the tumor microenvironment

Abstract Glioma is one of the most aggressive cancers and represents approximately 80% of malignant brain tumors. The majority of CNS World Health Organization (WHO) grades 2-3 gliomas and a subset of high-grade gliomas (CNS WHO grade 4) harbor mutated isocitrate dehydrogenase 1 (IDH1R132H; mIDH1). Mutant IDH1 results in the accumulation of 2-hydroxyglutarate (2HG) which elicits profound changes in the glioma transcriptome/biology. Consequently, mIDH1 glioma patients have a significantly increased median survival compared to wildtype IDH1 patients. Recent data from our lab showed that mIDH1 gliomas exhibit increased immune-reactivity of tumor-infiltrating immune cells. A critical pathway that mediates reduction of anti-tumor immune cell reactivity is the adenosinergic pathway (AP), which converts ATP into adenosine via the enzymes CD39 and CD73. Adenosine binds to adenosine receptors, A2AR and A2BR, on immune cells resulting in a decreased immunoreactivity. Although mIDH1 has been implicated in altering the AP, the extent to which the AP is affected by mIDH1 in gliomas is largely unknown. Here we used human and mouse mIDH1 glioma cells in vitro along with in vivo mIDH1 glioma mouse models to examine changes in the AP. Our results show reduced levels of the enzyme, CD73, on the surface of mIDH1 glioma cells, and the ATP concentration in the mIDH1 glioma cell growth media is lower than from wildtype IDH1 glioma cells. Additionally, we discovered that mIDH1 glioma-infiltrating macrophages have decreased expression of CD39 and A2AR compared to their wildtype IDH1 glioma counterparts. Taken together, these data suggest a reduction of the AP mediated-immune suppression in mIDH1 gliomas. Uncovering these differences in the AP provides novel insights on the use of AP inhibitors for glioma treatment, revealing whether the AP is a preferred target in specific glioma types based on the IDH1 mutation status.