Potent immunosuppressive effects of the oncometabolite R-2-hydroxyglutarate.

Abstract:

:Somatic gain-of-function mutations in isocitrate dehydrogenase (NADP(+)) 1, cytosolic (IDH1) or isocitrate dehydrogenase (NADP(+)) 2, mitochondrial (IDH2) are bona fide oncogenic drivers of acute myeloid leukemia and glioma because the neomorphic enzymes catalyze the synthesis of R-2-hydroxylutarate (R-2-HG), an oncometabolite with robust epigenetic effects. Recent data indicate that R-2-HG released by malignant cells can accumulate in the extracellular space and be taken up by T lymphocytes, ultimately compromising their capacity to mediate anticancer immune responses. Thus, R-2-HG drives oncogenesis and tumor progression not only as a cancer cell-autonomous epigenetic modifier, but also as an immunosuppressive metabolite. Chemical inhibitors of mutant IDH1 and IDH2, which currently are under clinical evaluation, may therefore mediate dual anticancer effects by targeting cancer cells and, at the same time, relieving R-2-HG-mediated immunosuppression.

journal_name

Oncoimmunology

journal_title

Oncoimmunology

authors

Galluzzi L,Kroemer G

doi

10.1080/2162402X.2018.1528815

subject

Has Abstract

pub_date

2018-10-16 00:00:00

pages

e1528815

issue

12

eissn

2162-4011

issn

2162-402X

pii

1528815

journal_volume

7

pub_type

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