Inhibition of 2-hydroxyglutarate elicits metabolic reprogramming and mutant IDH1 glioma immunity in mice

• Published in: The Journal of clinical investigation Vol. 131; no. 4; pp. 1 - 20
• Main Authors: Kadiyala, Padma, Carney, Stephen V, Gauss, Jessica C, Garcia-Fabiani, Maria B, Haase, Santiago, Alghamri, Mahmoud S, Núñez, Felipe J, Liu, Yayuan, Yu, Minzhi, Taher, Ayman, Nunez, Fernando M, Li, Dan, Edwards, Marta B, Kleer, Celina G, Appelman, Henry, Sun, Yilun, Zhao, Lili, Moon, James J, Schwendeman, Anna, Lowenstein, Pedro R, Castro, Maria G
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 15.02.2021
• Subjects: Apoptosis; Autophagy; Biomedical research; Brain cancer; Care and treatment; CD8 antigen; Dehydrogenases; Development and progression; Gene mutations; Genetic aspects; Glioma; Glioma cells; Gliomas; Health aspects; Immune checkpoint; Immunological memory; Immunology; Intellectual disabilities; Isocitrate dehydrogenase; Lymphocytes; Lymphocytes T; Memory cells; Metabolism; Mutants; Mutation; Oxidoreductases; p53 Protein; PD-L1 protein; Proteins; Radiation therapy; Temozolomide; Thalassemia; Tumor microenvironment; United States; Neuroscience; Adaptive immunity; Immunology; Brain cancer; Immunotherapy
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI139542

Mutant isocitrate dehydrogenase 1 (IDH1-R132H; mIDH1) is a hallmark of adult gliomas. Lower grade mIDH1 gliomas are classified into 2 molecular subgroups: 1p/19q codeletion/TERT-promoter mutations or inactivating mutations in α-thalassemia/mental retardation syndrome X-linked (ATRX) and TP53. This work focuses on glioma subtypes harboring mIDH1, TP53, and ATRX inactivation. IDH1-R132H is a gain-of-function mutation that converts α-ketoglutarate into 2-hydroxyglutarate (D-2HG). The role of D-2HG within the tumor microenvironment of mIDH1/mATRX/mTP53 gliomas remains unexplored. Inhibition of D-2HG, when used as monotherapy or in combination with radiation and temozolomide (IR/TMZ), led to increased median survival (MS) of mIDH1 glioma-bearing mice. Also, D-2HG inhibition elicited anti-mIDH1 glioma immunological memory. In response to D-2HG inhibition, PD-L1 expression levels on mIDH1-glioma cells increased to similar levels as observed in WT-IDH gliomas. Thus, we combined D-2HG inhibition/IR/TMZ with anti-PDL1 immune checkpoint blockade and observed complete tumor regression in 60% of mIDH1 glioma-bearing mice. This combination strategy reduced T cell exhaustion and favored the generation of memory CD8+ T cells. Our findings demonstrate that metabolic reprogramming elicits anti-mIDH1 glioma immunity, leading to increased MS and immunological memory. Our preclinical data support the testing of IDH-R132H inhibitors in combination with IR/TMZ and anti-PDL1 as targeted therapy for mIDH1/mATRX/mTP53 glioma patients.