학술논문
Inhibition of 2-hydroxyglutarate elicits metabolic reprogramming and mutant IDH1 glioma immunity in mice.
Document Type
Journal Article
Author
Kadiyala, Padma; Carney, Stephen V.; Gauss, Jessica C.; Garcia-Fabiani, Maria B.; Haase, Santiago; Alghamri, Mahmoud S.; Núñez, Felipe J.; Yayuan Liu; Minzhi Yu; Taher, Ayman; Nunez, Fernando M.; Dan Li; Edwards, Marta B.; Kleer, Celina G.; Appelman, Henry; Yilun Sun; Lili Zhao; Moon, James J.; Schwendeman, Anna; Lowenstein, Pedro R.
Source
Subject
*GLIOMAS
*ISOCITRATE dehydrogenase
*GAIN-of-function mutations
*IMMUNOLOGIC memory
*FETAL hemoglobin
*GLIOMA treatment
*CELL differentiation
*PROTEINS
*RESEARCH
*ANIMAL experimentation
*RESEARCH methodology
*MEDICAL cooperation
*EVALUATION research
*COMPARATIVE studies
*IMMUNITY
*RESEARCH funding
*ACYCLIC acids
*T cells
*CELL lines
*OXIDOREDUCTASES
*MICE
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Language
ISSN
0021-9738
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. [ABSTRACT FROM AUTHOR]