IDH-Mutant Brain Tumors Hit the Achilles’ Heel of Macrophages with R-2-Hydroxyglutarate

Abstract

Isocitrate dehydrogenase (IDH) mutations produce high levels of the ‘oncometabolite’ R-2-hydroxyglutarate (R-2-HG) and play a key role in the initiation and progression of glioma tumors in the brain. A recent study in Nature Cancer by Friedrich et al. describes how IDH-mutant-derived R-2-HG elicits an immunosuppressive phenotype in glioma-associated macrophages. As such, the authors uncovered a new vulnerability that can be exploited for therapy. Isocitrate dehydrogenase (IDH) mutations produce high levels of the ‘oncometabolite’ R-2-hydroxyglutarate (R-2-HG) and play a key role in the initiation and progression of glioma tumors in the brain. A recent study in Nature Cancer by Friedrich et al. describes how IDH-mutant-derived R-2-HG elicits an immunosuppressive phenotype in glioma-associated macrophages. As such, the authors uncovered a new vulnerability that can be exploited for therapy. Originating from glial cells, gliomas belong to the most common and lethal types of brain cancer and are often accompanied by a poor prognosis. Overall, the immunosuppressive tumor microenvironment (TME) can restrict antitumor immunity. Since metabolic rewiring directly regulates immune responses, metabolic communication between tumors and key immune cells, like macrophages and T cells, shapes this TME. Among the most frequent mutations occurring in gliomas are mutations in the active site of the metabolic Krebs cycle enzyme isocitrate dehydrogenase 1 (IDH1). These mutations lead to a gain of IDH1 function and subsequent de novo production of the oncometabolite R-2-hydroxyglutarate (R-2-HG) [1.Parsons D.W. et al.An integrated genomic analysis of human glioblastoma multiforme.Science. 2008; 321: 1807-1812Crossref PubMed Scopus (4271) Google Scholar,2.Dang L. et al.Cancer-associated IDH1 mutations produce 2-hydroxyglutarate.Nature. 2009; 462: 739-744Crossref PubMed Scopus (2357) Google Scholar]. IDH1 mutations and consequent R-2-HG induction appear to have dual effects on tumorigenesis and progression. Detrimental effects of R-2-HG include: (i) induction of epigenetic changes that contribute to tumorigenesis, and (ii) suppression of antitumor T cell responses [3.Bunse L. et al.Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate.Nat. Med. 2018; 24: 1192-1203Crossref PubMed Scopus (145) Google Scholar]. Conversely, R-2-HG exhibits antiproliferative effects in cancer cells, and patients with IDH-mutant gliomas have a survival benefit over patients with IDH-wild-type (IDH-WT) gliomas [1.Parsons D.W. et al.An integrated genomic analysis of human glioblastoma multiforme.Science. 2008; 321: 1807-1812Crossref PubMed Scopus (4271) Google Scholar,4.Bralten L.B. et al.IDH1 R132H decreases proliferation of glioma cell lines in vitro and in vivo.Ann. Neurol. 2011; 69: 455-463Crossref PubMed Scopus (111) Google Scholar]. As such, a clearer understanding of different effects of R-2-HG in the TME is expected to yield better therapy opportunities. In a new study in Nature Cancer, Friedrich et al. provide new insights into how R-2-HG elicits suppressive glioma-associated macrophages (GAMs), opening up new avenues for intervention [5.Friedrich M. et al.Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas.Nat. Cancer. 2021; (Published online May 24, 2021. https://doi.org/10.1038/s43018-021-00201-z)Crossref Scopus (13) Google Scholar]. Friedrich and colleagues explored the different immune cell populations present in the TME of human gliomas [5.Friedrich M. et al.Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas.Nat. Cancer. 2021; (Published online May 24, 2021. https://doi.org/10.1038/s43018-021-00201-z)Crossref Scopus (13) Google Scholar]. Using single-cell RNA-sequencing and mass cytometry, they demonstrated that myeloid cells from patients with IDH-mutant gliomas showed lower expression of antigen presentation-associated proteins, suggesting a more immunosuppressive phenotype in comparison with IDH-WT GAMs. To further investigate the dynamics and genotype-dependent effects of the TME on the immunosuppressive phenotype of myeloid cells, the authors overexpressed WT or mutant IDH in the GL261 mouse glioma model. Initially, IDH-mutant gliomas contained more microglia with an attenuated activation profile and less infiltrating monocyte-derived macrophages, but the latter markedly increased over time during tumor progression in comparison with IDH-WT. Since the transcriptional profile of these myeloid cell subsets suggested a reduced antigen presentation capacity in IDH-mutant gliomas, the authors next turned to ex vivo cocultures to confirm that macrophages infiltrating IDH-mutant gliomas suppress T cells via IDH-mutant-derived R-2-HG. The authors further elucidated the complex underlying mechanism by demonstrating the involvement of the aryl-hydrocarbon receptor (AHR). Following exposure to R-2-HG in macrophages, AHR translocated into the nucleus, resulting in an AHR-dependent increase of the anti-inflammatory cytokines interleukin (IL)-10 and transforming growth factor (TGF)-β, further underlining the immunosuppressive macrophage phenotype in IDH-mutant tumors (Figure 1). Strikingly, R-2-HG was not a direct inducer of AHR translocation. Instead, R-2-HG increased the tryptophan-2,3-dioxygenase (TDO)-2-mediated conversion of intracellular l-tryptophan (l-Trp) to the endogenous AHR ligand l-kynurenine (l-Kyn). In response, macrophages increased the uptake of l-Trp via the LAT-1/CD98 heterodimer, which was upregulated in macrophages from IDH-mutant compared with IDH-WT tumors. The increased catabolism of l-Trp is seemingly unique to macrophages and thereby uncovers a metabolic vulnerability of GAM to IDH-mutant-derived R-2-HG. This specific susceptibility could be partially overcome by using an AHR inhibitor in tumor-bearing mice, inducing prolonged survival of IDH-mutant, but not WT, tumor-bearing mice. Yet, it should be noted that mice bearing IDH-mutant tumors showed reduced survival in this experimental setting, whereas patients with IDH-mutant gliomas mostly show improved prognosis [1.Parsons D.W. et al.An integrated genomic analysis of human glioblastoma multiforme.Science. 2008; 321: 1807-1812Crossref PubMed Scopus (4271) Google Scholar]. While Friedrich et al. show that IDH-mutant gliomas educate their infiltrating macrophages toward an immunosuppressive phenotype [5.Friedrich M. et al.Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas.Nat. Cancer. 2021; (Published online May 24, 2021. https://doi.org/10.1038/s43018-021-00201-z)Crossref Scopus (13) Google Scholar], the question remains, how do these findings translate to the situation in patients [1.Parsons D.W. et al.An integrated genomic analysis of human glioblastoma multiforme.Science. 2008; 321: 1807-1812Crossref PubMed Scopus (4271) Google Scholar]? Although IDH mutations may contribute to tumorigenesis by blocking differentiation of progenitor cells via epigenetic mechanisms [6.Lu C. et al.IDH mutation impairs histone demethylation and results in a block to cell differentiation.Nature. 2012; 483: 474-478Crossref PubMed Scopus (1291) Google Scholar], they correlate with improved prognosis in established gliomas [1.Parsons D.W. et al.An integrated genomic analysis of human glioblastoma multiforme.Science. 2008; 321: 1807-1812Crossref PubMed Scopus (4271) Google Scholar]. While the exact mechanisms of this prolonged overall survival are currently unknown, selective inhibitors targeting mutant IDH decrease both R-2-HG levels and tumor growth [7.Rohle D. et al.An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells.Science. 2013; 340: 626-630Crossref PubMed Scopus (796) Google Scholar]. As R-2-HG appears to exert dual effects, specifically targeting its detrimental consequences could contribute to an improved prognosis for IDH-mutated gliomas. One such strategy could be targeting R-2-HG-mediated AHR activation, potentially counteracting unfavorable immunosuppression of GAMs while leaving other benign mechanisms intact. Since R-2-HG also affects T cells (demonstrated in an earlier study from the Platten laboratory [3.Bunse L. et al.Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate.Nat. Med. 2018; 24: 1192-1203Crossref PubMed Scopus (145) Google Scholar]) and other cells within the TME, an important question that remains to be answered is which IDH-mutant-associated mechanisms are dominant and how might these mechanisms change over time or with tumor grade? Resolving this puzzle will aid in dissecting the diverse effects of IDH-mutations and subsequent R-2-HG induction on tumor progression. By uncovering the mechanism of R-2HG-mediated suppression in macrophages, Friedrich et al. solved an important piece of the puzzle and revealed altered tryptophan handling in macrophages as a metabolic vulnerability that should be further tested for the treatment of patients with IDH-mutant gliomas. No interests are declared.

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