Inhibition of 2-hydroxyglutarate elicits metabolic reprogramming and mutant IDH1 glioma immunity in mice
Padma Kadiyala, … , Pedro R. Lowenstein, Maria G. Castro
Padma Kadiyala, … , Pedro R. Lowenstein, Maria G. Castro
Published December 17, 2020
Citation Information: J Clin Invest. 2021;131(4):e139542. https://doi.org/10.1172/JCI139542.
View: Text | PDF
Research Article Immunology Neuroscience

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

Abstract

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.

Authors

Padma Kadiyala, Stephen V. Carney, Jessica C. Gauss, Maria B. Garcia-Fabiani, Santiago Haase, Mahmoud S. Alghamri, Felipe J. Núñez, Yayuan Liu, Minzhi Yu, Ayman Taher, Fernando M. Nunez, Dan Li, Marta B. Edwards, Celina G. Kleer, Henry Appelman, Yilun Sun, Lili Zhao, James J. Moon, Anna Schwendeman, Pedro R. Lowenstein, Maria G. Castro

×

Figure 2

Inhibition of IDH1-R132H decreases the production of D-2HG in vivo, improves the survival of mIDH1 glioma–bearing mice, and elicits immunological memory.

Options: View larger image (or click on image) Download as PowerPoint
Inhibition of IDH1-R132H decreases the production of D-2HG in vivo, impr...
(A) Experimental design to assess D-2HG concentration in the brain TME. At 27 dpi brains were harvested for UPLC-MS analysis of D-2HG in the TME of normal mice (black), WT-IDH glioma–bearing mice (blue), mIDH1 glioma–bearing mice (red), and mIDH1 glioma–bearing mice treated with AGI-5198 (purple). (B) Quantification of D-2HG concentration in normal brain, mIDH1 tumor–bearing brain, WT-IDH tumor–bearing brain, and mIDH1 tumor–bearing brain plus AGI-5198 treatment. ****P < 0.0001, 2-way ANOVA. Bars represent mean ± SEM (n = 3 biological replicates). (C) AGI-5198+IR treatment inhibits mIDH1 glioma cell proliferation in vivo. Mitotic cell division (mitotic index) in mIDH1 glioma was assessed by the phosphorylation status of Ser10 in Histone 3 (pH3). Proliferation (S phase) of mIDH1 glioma was assessed by measuring the amount of EdU incorporation. Representative histograms display pH3- or EdU-positive cells (red, saline; black, IR; light blue, AGI-5198; gray, AGI-5198 + IR). ***P < 0.001, 1-way ANOVA. Bars represent mean ± SEM (n = 3 biological replicates). (D) Experimental design to assess the survival of mIDH1 glioma–bearing mice treated with AGI-5198 therapy in combination with radiation. (E) Kaplan-Meier analysis of mice treated with saline (n = 7), IR (n = 6), AGI-5198 (n =10), or AGI-5198+IR (n = 10). (F) Kaplan-Meier plot for rechallenged long-term survivors from (D) AGI-5198 (n = 4) or AGI-5198+IR (n = 4), and untreated animals (n = 6). Data were analyzed using the log-rank (Mantel-Cox) test. *P < 0.05; ***P < 0.001; ****P < 0.0001.