Mutant Isocitrate Dehydrogenase I in Glioma Cells Decreases Adenosinergic Pathway Signaling in Glioma Tumor Microenvironment

Abstract

Gliomas are the most common malignant brain tumors in adults 1. Low-grade gliomas (LGGs) are defined by the World Health Organization (WHO) grades I and II 2. The WHO restructured the classification of tumors of the nervous system in 2021, focusing on mutations in the isocitrate dehydrogenase 1 (IDH1) gene 3. The R132H mutation of IDH1 results in the reduction of α-ketoglutarate (αKG) to 2-hydroxyglutarate (2HG) 4. 2HG has various effects on the tumor microenvironment and its signaling pathways 5. The adenosinergic pathway is used to control tumor immune response 6. Under normal physiological conditions, cellular damage causes the release of extracellular adenosine triphosphate (ATP), which binds to immune P2X7 receptors to trigger inflammatory antitumor responses 7. However, tumors have adapted to turn extracellular ATP into anti-inflammatory adenosine (ADO) with the use of the adenosinergic pathway (AP), which allows them to avoid the antitumor responses 8. Integral to the adenosinergic pathway are the receptors CD39 and CD73, the former of which is used to dephosphorylate ATP to adenosine diphosphate (ADP) and further to adenosine monophosphate (AMP), and the latter is used to hydrolyze the last phosphate on AMP to convert it to adenosine 8. In an effort to analyze changes in the adenosinergic pathway due to mutant IDH1 (mIDH1), as well as the effect of mIDH1 on the expression of certain markers in T cells, we looked at CD73 and ATP expression in glioma cells and immune cells. It was observed that the secretion of ATP as well as the expression of CD73 was decreased in mIDH1 glioma cells. CD73 expression was increased in mIDH1 immune cells in the tumor microenvironment. These results lend themselves to the possibility of novel immunotherapies for the treatment of mIDH1 glioma patients using treatments that target adenosinergic pathway molecules.