Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate

Bunse, Lukas; Pusch, Stefan; Bunse, Theresa; Sahm, Felix; Sanghvi, Khwab; Friedrich, Mirco; Alansary, Dalia; Sonner, Jana K.; Green, Edward; Deumelandt, Katrin; Kilian, Michael; Neftel, Cyril; Uhlig, Stefanie; Keßler, Tobias; Landenberg, Anna von; Berghoff, Anna Sophie; Marsh, Kelly; Steadman, Mya; Zhu, Dongwei; Nicolay, Brandon; Wiestler, Benedikt; Breckwoldt, Michael O.; Al‐Ali, Ruslan; Karcher-Bausch, Simone; Bozza, Matthias; Oezen, Iris; Kramer, Magdalena; Meyer, J.; Habel, Antje; Eisel, Jessica; Poschet, Gernot; Weller, Michael; Nadji-Ohl, Minou; Thon, Niklas; Burger, Michael C.; Harter, Patrick N.; Ratliff, Miriam; Harbottle, Richard P.; Benner, Axel; Schrimpf, Daniel; Okun, Jürgen G.; Herold‐Mende, Christel; Turcan, Şevin; Kaulfuß, Stefan; Hess‐Stumpp, Holger; Bieback, Karen; Cahill, Daniel P.; Plate, Karl H.; Hänggi, Daniel; Dorsch, Marion; Suvà, Mario L.; Niemeyer, Barbara A.; Deimling, Andreas von; Wick, Wolfgang; Platten, Michael

doi:10.1038/s41591-018-0095-6

Cited by 377 publications

(329 citation statements)

References 69 publications

Supporting

Mentioning

314

Contrasting

Unclassified

Order By: Relevance

“…IDH has been shown to be mutated in 10% of primary GBM, but in as many as 90% secondary GBMs (70). It has recently been demonstrated that the IDH mutation IDH R132H results in the production of the oncometabolite (D) 2-hydroxygluterate (2HG), which directly modulates the TME reducing chemo-attractants responsible for the recruitment of TILs and limiting the function of NK cells (71)(72)(73). More studies are in necessary to address other potential mechanisms by which IDH R132H and its oncometabolite, 2HG, modulate the TME in GBM.…”

Section: Idhmentioning

confidence: 99%

Brain Tumor Microenvironment and Host State: Implications for Immunotherapy

Tomaszewski

Sánchez-Pérez

Gajewski

et al. 2019

Clinical Cancer Research

219

197

View full text Add to dashboard Cite

Glioblastoma (GBM) is a highly lethal brain tumor with poor responses to immunotherapies that have been successful in more immunogenic cancers with less immunosuppressive tumor microenvironments (TME). The GBM TME is uniquely challenging to treat due to tumor cellextrinsic components that are native to the brain, as well as tumor-intrinsic mechanisms that aid in immune evasion. Lowering the barrier of immunosuppression by targeting the genetically stable tumor stroma presents opportunities to treat the tumor in a way that circumvents the complications of targeting a constantly mutating tumor with tumor antigen-directed therapies. Tumor-associated monocytes, macrophages, and microglia are a stromal element of particular interest. Macrophages and monocytes compose the bulk of infiltrating immune cells and are considered to have protumor and immunosuppressive effects. Targeting these cells or other stromal elements is expected to convert what is considered the "cold" TME of GBM to a more "hot" TME phenotype. This conversion could increase the effectiveness of what have become conventional frontline immunotherapies in GBM-creating opportunities for better treatment through combination therapy.

show abstract

Section: Idhmentioning

confidence: 99%

Brain Tumor Microenvironment and Host State: Implications for Immunotherapy

Tomaszewski

Sánchez-Pérez

Gajewski

et al. 2019

Clinical Cancer Research

219

197

View full text Add to dashboard Cite

show abstract

“…A recent study suggests that the D-2HG directly inhibits anti-glioma CD8 T cells' functions in mIDH1 glioma TME (42). However, previous reports have shown that D-2HG is poorly cellpermeable (9,43).…”

Section: Discussionmentioning

confidence: 98%

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

Kadiyala

Carney

Gauss

et al. 2020

Preprint

View full text Add to dashboard Cite

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)...

show abstract

“…R-2HG interferes with the activation of the nuclear factor of activated T cells 1 (NFATC1), a key transcription factor (18). Interestingly, this effect is linked to ATP deficiency since it was rescued by a cell-permeable analog of ATP.…”

Section: Hg In Prevention Of Immunosurveillancementioning

confidence: 99%

“…Interestingly, this effect is linked to ATP deficiency since it was rescued by a cell-permeable analog of ATP. R-2HG also acts at the biochemical level in T cells inhibiting ornithine decarboxylase (18). As a result, the biosynthesis of polyamines such as putrescine is hampered.…”

Section: Hg In Prevention Of Immunosurveillancementioning

confidence: 99%

2-Hydroxyglutarate in Cancer Cells

Ježek

2020

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

Significance: Cancer cells are stabilized in an undifferentiated state similar to stem cells. This leads to profound modifications of their metabolism, which further modifies their genetics and epigenetics as malignancy progresses. Specific metabolites and enzymes may serve as clinical markers of cancer progression. Recent Advances: Both 2-hydroxyglutarate (2HG) enantiomers are associated with reprogrammed metabolism, in grade III/IV glioma, glioblastoma, and acute myeloid leukemia cells, and numerous other cancer types, while acting also in the cross talk of tumors with immune cells. 2HG contributes to specific alternations in cancer metabolism and developed oxidative stress, while also inducing decisions on the differentiation of naive T lymphocytes, and serves as a signal messenger in immune cells. Moreover, 2HG inhibits chromatin-modifying enzymes, namely 2-oxoglutarate-dependent dioxygenases, and interferes with hypoxia-inducible factor (HIF) transcriptome reprogramming and mammalian target of rapamycin (mTOR) pathway, thus dysregulating gene expression and further promoting cancerogenesis. Critical Issues: Typically, heterozygous mutations within the active sites of isocitrate dehydrogenase isoform 1 (IDH1) R132H and mitochondrial isocitrate dehydrogenase isoform 2 (IDH2) R140Q provide cells with millimolar r-2-hydroxyglutarate (r-2HG) concentrations, whereas side activities of lactate and malate dehydrogenase form submillimolar s-2-hydroxyglutarate (s-2HG). However, even wild-type IDH1 and IDH2, notably under shifts toward reductive carboxylation glutaminolysis or changes in other enzymes, lead to ''intermediate'' 0.01-0.1 mM 2HG levels, for example, in breast carcinoma compared with 10-8 M in noncancer cells. Future Directions: Uncovering further molecular metabolism details specific for given cancer cell types and sequence-specific epigenetic alternations will lead to the design of diagnostic approaches, not only for predicting patients' prognosis or uncovering metastases and tumor remissions but also for early diagnostics. Antioxid. Redox Signal. 00, 000-000.

show abstract

Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate

Cited by 377 publications

References 69 publications

Brain Tumor Microenvironment and Host State: Implications for Immunotherapy

Brain Tumor Microenvironment and Host State: Implications for Immunotherapy

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

2-Hydroxyglutarate in Cancer Cells

Contact Info

Product

Resources

About