LAUSR

Great excitement has been generated around the identification of tumor-specific hotspot mutations in isocitrate dehydrogenase I (IDH1) as they are the first potential 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 devastating tumors that are invariably recurrent and confer a dismal prognosis in their most aggressive forms. In addition to their high frequency of mutation in gliomas, 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 the oncometabolite D-2-hydroxyglutarate (D-2HG), which mediates many of mutant IDH1’s effects including blocks to normal differentiation, aberrant histone and DNA methylation profiles, perturbed metabolism, induction of an immunosuppressive microenvironment, among others. To gain an understanding of mutant IDH-mediated tumorigenesis, we generated genetically faithful mouse models of glioma that harbor the pathognomonic signature including the IDH1-R132H mutation and p53 deletion. This orthotopic intracranial injection 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 glioma 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 plasma cells, NK cells, monocytes, and M2 macrophages, while a subtle increase among dendritic cells was observed as indicated through immune deconvolution of RNAseq data of murine brain tumors. Further analysis showed a reduced Th17 gene expression profile that was corroborated through in vitro studies showing a D-2HG-mediated suppression of IL17 producing Th17 cells and a perturbed metabolic activity skewing towards oxidative phosphorylation. Th17 cells have only relatively recently been identified and their biological impact 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 understanding this understudied lineage and exposing 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 and anti-tumor activity of Th17 restoration or IL17 overproduction are actively being investigated. Citation Format: Nathan M. Reynolds, Ashleigh J. Soedel, Ximena Bustamante-Marin, Emily Z. Miller, Paula K. Greer, David M. Ashley, Yiping He, Matthew S. Waitkus, Christopher J. Pirozzi. Mutant IDH-mediated suppression of the Th17 lineage in glioma: Biologic impact and therapeutic potential [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1261.