D-2-hydroxyglutarate interferes with HIF-1α stability skewing T-cell metabolism towards oxidative phosphorylation and impairing Th17 polarization
Open accessAbstract
D-2-hydroxyglutarate (D-2HG) is released by various types of malignant cells including acute myeloid leukemia (AML) blasts carrying isocitrate dehydrogenase (IDH) gain-of-function mutations. D-2HG acting as an oncometabolite promotes proliferation, anoikis, and differentiation block of hematopoietic cells in an autocrine fashion. However, prognostic impact of IDH mutations and high D-2HG levels remains controversial and might depend on the overall mutational context. An increasing number of studies focus on the permissive environment created by AML blasts to promote immune evasion. Impact of D-2HG on immune cells remains incompletely understood. Here, we sought out to investigate the effects of D-2HG on T-cells as key mediators of anti-AML immunity. D-2HG was efficiently taken up by T-cells in vitro, which is in line with high 2-HG levels measured in T-cells isolated from AML patients carrying IDH mutations. T-cell activation was slightly impacted by D-2HG. However, D-2HG triggered HIF-1a protein destabilization resulting in metabolic skewing towards oxidative phosphorylation, increased regulatory T-cell (Treg) frequency, and reduced T helper 17 (Th17) polarization. Our data suggest for the first time that D-2HG might contribute to fine tuning of immune responses.
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Different enantiomeric forms of 2-HG may induce different responses to hypoxia, including a HIF-independent one and an altogether different tumour phenotype.
“The different enantiomeric forms of 2-HG may thus induce different responses to hypoxia, including a HIF-independent one and an altogether different tumour phenotype.”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [156]
The Results section (page unavailable) reports that D-2HG reduced HIF-1α protein and Th17 polarization in T-cells, while the S-enantiomer did not reproduce those effects. The Discussion contrasts D-2HG findings with a reported S-2HG effect in murine T-cells under hypoxia. These passages support different effects of the enantiomers, but not a HIF-independent response or an altogether different tumour phenotype. (LLM, conf=0.82)
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- Authors
- Böttcher, M., Renner, K., Berger, R., Mentz, K., Thomas, S., Cardenas-Conejo, Z. E., Dettmer, K., Oefner, P. J., Mackensen, A., Kreutz, M., & Mougiakakos, D.
- Affiliations
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- University Hospital Regensburg (DE)
- University of Regensburg (DE)
- Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany
- Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany
- Corresponding author
- Böttcher, Martin
- ORCID
- Venue
- OncoImmunology
- Publisher
- Informa UK Limited
- Published
- 2018-03-26
- Volume
- 7
- Issue
- 7
- Pages
- e1445454
- ISSN
- 2162-4011 (ISSN-L)
- 2162-402X
- PMC
- PMC5993507
- OpenAlex
- W2790027255
- Cited by
- 124
- References
- 69
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 23 · 2023: 12 · 2022: 20 · 2021: 15 · 2020: 16 · 2019: 16 · 2018: 5
- FWCI
- 3.93
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- OncoImmunology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- University of Regensburg Publication Server (University of Regensburg) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- University of Regensburg Publication Server (University of Regensburg)
- Funders
- IZKF Erlangen (Project D27)
- CDC/TR221 (DFG) (Project A06)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- D-2-hydroxyglutarate, IDH mutation, acute myeloid leukemia, oncometabolites, T cell metabolism, oxidative phosphorylation, Th17 polarization, regulatory T cells, T cell activation, immune evasion
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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