Inhibition of 2-Hydroxyglutrate Elicits Metabolic-reprograming and Mutant IDH1 Glioma Immunity

Abstract

Brief Summary: Inhibition of 2-Hydroxyglutrate in mutant-IDH1 glioma in the genetic context of ATRX and TP53 inactivation elicits metabolic-reprograming and anti-glioma immunity. Abstract:Mutant isocitrate-dehydrogenase-1 (IDH1-R132H; mIDH1) is a hallmark of adult gliomas.Lower grade mIDH1 gliomas are classified into two molecular subgroups: (i) 1p/19q codeletion/TERT-promoter mutations or (ii) inactivating mutations in α-thalassemia/mental retardation syndrome X-linked (ATRX) and TP53. This work, relates to the gliomas' subtype 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 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, 2HG inhibition elicited anti-mIDH1 glioma immunological memory. In response to 2HG inhibition, PD-L1 expression levels on mIDH1-glioma cells increased to similar levels as observed in wild-type-IDH1 gliomas. Thus, we combined 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 supports the testing of IDH-R132H inhibitors in combination with IR/TMZ and anti-PDL1 as targeted therapy for mIDH1/mATRX/mTP53 glioma patients. Introduction:Gliomas are highly infiltrative brain tumors accounting for 32% of all primary central nervous system malignancies (1). With advances in molecular biology and sequencing technologies, a distinct profile of genetic alterations for gliomas has emerged (1-3). A gain-offunction mutation in the gene encoding isocitrate dehydrogenase 1 (IDH1) mutation has been reported in ~46% of all adult gliomas (2) and ~80% of low grade gliomas (3, 4). This mutation results in the replacement of arginine (R) for histidine (H) at amino acid residue 132 (R132H) (5, 6). In gliomas, the IDH1-R132H mutation co-occurs with the following genetic alterations: i) oligodendroglioma-1p/19q co-deletion, TERT promoter mutations, or ii) astrocytoma-inactivation of tumor suppressor protein 53 (TP53) gene and loss of function mutations in alpha thalassemia/mental retardation syndrome X-linked gene (ATRX) (2, 4, 7).The IDH1-R132H neomorphic mutation (mIDH1) confers a gain-of-function catalytic activity, prompting the NADPH-dependent reduction of alpha ketoglutarate (α-KG) to the oncometabolite D-2-hydroxyglutarate (2-HG) (5, 8,9). The accumulation of 2-HG acts antagonistically to α-KG, competitively inhibiting α-KG-dependent dioxygenases, including the ten-eleven translocation (TET) methylcytosine dioxygenases and Jumonji C (JmjC)...

Genetic Alterations in Gliomas Remodel the Tumor Immune Microenvironment and Impact Immune-Mediated Therapies

“…We also observed that mIDH1 glioma cells exhibit lower levels of PD-L1 expression ( 24 ). In response to (R)-2-HG inhibition, PD-L1 expression levels on mIDH1 glioma cells significantly increased to those observed in wild type IDH gliomas ( 24 ). Numerous preclinical solid tumor models have demonstrated that the immune checkpoint blockade of PD-1/PD-L1 interaction prevents T cell exhaustion, resulting in enhanced anti-tumor immune activity and improved MS ( 9 , 319 , 320 ).…”

“…Moreover, multiple studies have shown that the PD-L1 level can be regulated by epigenetic mechanisms. For example, in IDH1 mutated glioma, we have shown that methylation in PD-L1 promoter negatively correlates with PD-L1 expression and prognosis ( 24 ).…”

“…We recently demonstrated that in genetically engineered mIDH1 mouse gliomas, resembling human mutant IDH1 astrocytoma, (R)-2-HG inhibition in combination with SOC increased the infiltration of DCs and anti-tumor specific T cells in the TME, while decreasing the infiltration of immunosuppressive MDSCs, Tregs, and M2 macrophages compared to saline treated mice ( 24 ). We also observed that mIDH1 glioma cells exhibit lower levels of PD-L1 expression ( 24 ). In response to (R)-2-HG inhibition, PD-L1 expression levels on mIDH1 glioma cells significantly increased to those observed in wild type IDH gliomas ( 24 ).…”

“…Also, we will overview the present immune-stimulatory therapeutic modalities being tested in clinical trials (8,17). Finally, we will discuss the latest pre-clinical developments related to anti-glioma therapies that could enhance the immune system to develop long-lasting anti-tumor immunity (18)(19)(20)(21)(22)(23)(24).…”

Targeting Neuroinflammation in Brain Cancer: Uncovering Mechanisms, Pharmacological Targets, and Neuropharmaceutical Developments

“…Exhaustion is a hypo-responsive T-cell state resulting from chronic antigenic exposure under sub-optimal conditions. This state represents a specific transcriptional program that is often characterized by up-regulation of various co-inhibitory receptors including PD-1, LAG-3, and TIM-3, on the T cells ( Koyama et al, 2016 ; Kadiyala et al, 2020 ; Mohme and Neidert, 2020 ). These exhausted CD8 + T cells (CD8 + T ex cells) have lower secretion of their effector cytokines, but they still provide some, albeit reduced antitumor immunity ( Woroniecka et al, 2018 ).…”