Cited by 124Cancer, Hypoxia, and MetabolismAcute Myeloid Leukemia ResearchImmune cells in cancer

D-2-hydroxyglutarate interferes with HIF-1α stability skewing T-cell metabolism towards oxidative phosphorylation and impairing Th17 polarization

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Böttcher, Martin, Renner, Kathrin, Berger, Raffaela, Mentz, Kristin, Thomas, Simone, Cardenas-Conejo, Zugey Elizabeth, Dettmer, Katja, Oefner, Peter J. +3 more·2018·OncoImmunology

Abstract

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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Crossref · 10.1080/2162402x.2018.1445454

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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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  1. [45]Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, Chi H HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med. 2011; 208: 1367– 76. doi: 10.1084/jem.20110278. PMID:21708926. 21708926 PMC3135370 · DOI · Paper page

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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
Venue
OncoImmunology
Published
2018-03-26
Volume
7
Issue
7
Pages
e1445454
ISSN
  • 2162-4011 (ISSN-L)
  • 2162-402X
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
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

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