TMIC-07. MUTANT IDH-MEDIATED SUPPRESSION OF THE TH17 LINEAGE IN GLIOMA; BIOLOGIC IMPACT AND THERAPEUTIC POTENTIAL

Abstract

Abstract Great excitement has surrounded the identification of tumor-specific hotspot mutations in IDH1 as they are the first therapeutic targets of low grade gliomas that have been identified in the last several decades. With a low number of viable therapeutic targets, mutations in IDH1 represent new hope in treating these tumors that are invariably recurrent and confer a dismal prognosis in their aggressive forms. Additionally, mutations in IDH1 are tumor-specific suggesting their effective targeting can reduce the collateral damage to the normal brain imparted by standard therapies. Furthermore, mutations in IDH1 lead to the overproduction of D-2-hydroxyglutarate (D-2HG), which mediates many of mutant IDH1’s effects. To gain an understanding of mutant IDH-mediated tumorigenesis, we generated genetically faithful mouse models that harbor the pathognomonic signature including the IDH1-R132H mutation and p53 deletion. This model generates tumors that overproduce D-2HG, are histologically diffuse, and confer a prolonged survival compared to their wildtype counterparts. Additionally, these models display the proneural subtype and are enriched for an oligodendrocyte precursor cell gene expression signature, both of which are typified by IDH mutations in human glioma. Exploring the impact of the IDH mutation on the tumor microenvironment, we identified several diminished immune cell subsets among the mutant IDH murine tumors, including NK cells, monocytes, and M2 macrophages. Further analysis showed a reduced Th17 gene expression profile that was corroborated through in vitro studies. The biological impact of Th17 cells appears to be cancer-context dependent with only a few studies being performed in gliomas. With the potential for Th17-mediated anti-tumor activity, as observed in cases of melanoma, the prospect for elucidating a new therapeutic avenue is exciting. As such, the biological significance of D-2HG-mediated Th17 suppression, the underlying mechanism, as well as the therapeutic potential of Th17 restoration are actively being investigated.