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.
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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

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Figure 5

Inhibition of IDH1-R132H in combination with SOC and αPD-L1 exhibits enhanced survival of mIDH1 glioma–bearing mice.

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Inhibition of IDH1-R132H in combination with SOC and αPD-L1 exhibits enh...
(A) Experimental design to assess survival for AGI-5198+SOC+αPD-L1 therapy. (B) Kaplan-Meier survival analysis of C57BL/6 mice treated with saline (n = 5), SOC (n = 5), TMZ (n = 5), αPD-L1+SOC (n = 5), αPD-L1 (n = 5), αPD-L1+TMZ (n = 5), and IR+αPDL (n = 5). (C) Kaplan-Meier survival analysis of C57BL/6 mice treated with saline (n = 5), AGI-5198+TMZ+αPD-L1 (n = 5), AGI-5198+SOC (n = 5), AGI-5198+IR+αPD-L1 (n = 5), and AGI-5198+SOC+αPD-L1 (n = 5). (D) Kaplan-Meier survival plot for rechallenged long-term survivors from (C) AGI-5198+TMZ+αPD-L1 (n = 1), AGI-5198+SOC (n = 2), AGI-5198+IR+αPD-L1 (n = 2), and AGI-5198+SOC+αPD-L1 (n = 3) groups, and control mice (n = 3). Data were analyzed using the log-rank (Mantel-Cox) test. **P < 0.001; ***P < 0.001. (E) Kaplan-Meier analysis of mIDH1 glioma–bearing CD8-KO mice treated with saline (n = 5) or AGI-5198+SOC+αPD-L1 (n = 5). (G) C57BL/6 mice bearing mIDH1 glioma were treated with saline or AGI-5198+SOC+αPD-L1 as detailed in A. At 27 dpi, brains were harvested for immunohistochemistry analysis. Immunofluorescence staining for Ki67 and CC3 was performed on 50 μm vibratome tumor sections. Bar graphs represent total number of positive cells for Ki67 and CC3 in saline or AGI-5198+SOC+αPD-L1 treatment groups. **P < 0.01; ***P < 0.001, unpaired t test. Bars represent mean ± SEM (n = 3 biological replicates). (F) Nissl staining of 50 μm brain sections at 27 dpi from mIDH1 tumor–bearing mice treated with saline and AGI-5198+SOC+αPD-L1. ****P < 0.001; unpaired t test. Bars represent mean ± SEM (n = 3 biological replicates).