https://orcid.org/0000-0002-4490-7574
Astrocytomas and oligodendrogliomas, World Health Organization grades 2-4, are signified by recurrent mutations in the genes for mutant isocitrate dehydrogenase (IDH) types 1 and 2. The neomorphic enzymatic activity of mutant IDH causes epigenetic reprogramming by histone and DNA hypermethylation via the excessive production of the oncometabolite R-2-hydroxyglutarate (R-2-HG), ultimately driving dedifferentiation and malignant transformation. Therefore, small molecule mutant IDH inhibitors have been developed to re-differentiate glioma cells in early-stage gliomas.
In recent years, a plethora of data has been collected highlighting mutant IDH as a key suppressor of spontaneous and therapy-induced anti-glioma immunity. On the one hand, mutant IDH excludes T cells from the glioma microenvironment (GME) by inhibition of glioma cell signal transducer and activator of transcription 1 (STAT1) transcriptional activity followed by reduced C-X-C motif chemokine ligand 10 (CXCL10)-dependent recruitment of cytotoxic T cells. On the other, its neomorphic enzymatic product R-2-HG incapacitates yet infiltrating T cells by paracrine inhibition of calcium-dependent T cell receptor signaling and polyamine biosynthesis and induces apoptosis of intratumoral T cells.1–3
Exclusion of immune cells from the IDH-mutant GME is not restricted to adaptive immune cells. In experimental RCAS/tva-based IDH-mutant murine tumors, neutrophil chemotaxis is reduced compared to IDH-wildtype control tumor-bearing mice.4 In addition, recent advances in single-cell transcriptome and proteome profiling enabled the discovery of IDH genotype- and tumor subtype-specific education of myeloid cells in brain tumors.5,6 Especially in IDH-mutant gliomas, attenuated antigen presentation and cross-presentation signatures of monocyte-derived macrophages have been found. As one important underlying molecular mechanism, longitudinal and spatial R-2-HG-associated immunometabolic alterations in tryptophan catabolism have been linked to the reduced antigen presentation capacities of monocyte-derived macrophages, again resulting in reduced T-cell effector functions.7
Beyond IDH-dependent immunometabolic reprogramming, glioma cell-intrinsic hypermethylation of natural killer group 2D (NKG2D) ligands has been reported to mask IDH-mutant glioma cells, rendering them resistant to NK cell-mediated tumor cell killing. Thus, mutant IDH differentially compromises anti-glioma activity of multiple immune cell subsets including T cells, myeloid cells and NK cells.
In a recent study, Ludwig and colleagues identified another important mechanism how mutant IDH orchestrates the adaptive and innate immune systems on a local and on a systemic scale.8 The authors analyzed tumor-derived small extracellular vesicles (TEX) equipped with proteins, nucleic acids, and lipids from human IDH-mutant glioma stem cells (IDH mut-TEX) that share features with their parental cells. More importantly, these IDH mut-TEX have profound immunomodulatory effects on local and systemic immune environments (Figure 1).
How mutant isocitrate dehydrogenase orchestrates immune cells within the glioma microenvironment and in peripheral compartments. Figure created with BioRender.com.
In comparison to TEX isolated from human IDH-wildtype glioma stem cells, IDH mut-TEX were more abundant and enriched with immunosuppressive proteins such as transforming growth factor beta (TGF-β) and TNF-related apoptosis-inducing ligand (TRAIL). When administered retro-orbitally into C57BL/6 mice, TEX displayed strong brain penetration which was augmented in inflammatory conditions.
Interestingly, repetitive intravenous injections of IDH mut-TEX increased the proportion of circulating monocytes and decreased peripheral regulatory T cells in mice. To approach the question if TEX affect monocytic hematopoiesis or act directly on existing circulating immune cells, the authors performed ex vivo flow cytometric phenotyping of murine peripheral mononuclear cells followed by exposure to IDH mut-TEX and TEX derived from IDH-wildtype human glioma stem cells. Although this experimental setup has obvious limitations, the proportion of immunostimulatory M1 in vitro phenotypes of macrophages was strongly reduced and the proportion of immunoinhibitory M2 macrophages was increased after IDH mut-TEX exposure.
In an IDH-mutant and -wildtype immunocompetent mouse glioma model based on G12V-mutated neuroblastoma RAS viral oncogene homolog (NRAS) and knockdown of alpha thalassemia/mental retardation syndrome X-linked (Atrx) and tumor suppressor p53 (Tp53), the authors show reduced survival of animals after systemic administration of IDH mut-TEX.
Analysis of tumor-infiltrating leukocytes from IDH mut-TEX-treated animals showed increased proportions of immunosuppressive myeloid populations such as myeloid-derived suppressor cells and of regulatory T cells. Similar to observations in non-tumor-bearing mice, IDH mut-TEX specifically reprogrammed the peripheral immune landscape, resulting in reduced proportions of NK cells, dendritic cells (DCs), and macrophages compared to control animals.
Overall, these findings suggest an important IDH genotype-dependent immune regulatory effect of TEX uniquely equipped when derived from IDH-mutant glioma cells. The utilization of human glioma stem cells in this study is suggestive for a clinically relevant immunosuppressive phenomenon beyond the preclinical mouse glioma models applied in this study. In conjunction with the above-mentioned tumor intrinsic and extrinsic immunosuppressive capacities of mutant IDH and the numerous reports of endogenous and therapy-induced systemic immunosuppression in glioma patients, this novel concept has important implications for immunotherapeutic approaches such as targeting mutant IDH by vaccination in patients with astrocytoma or oligodendroglioma.9,10 On a broader scale, the elegant study by Ludwig and colleagues alters our view on the IDH-mutant GME now potentially extending to peripheral immune compartments.
Acknowledgments
This editorial is the sole product of the authors and no third party had input or gave support to its writing.
Funding
This work was supported by Else Kröner-Fresenius Foundation, 2019_EKMS.49.
