New insights into the Immune TME of adult-type diffuse gliomas

Abstract

Purpose of review: Adult-type diffuse gliomas are highly heterogeneous tumors. Bulk transcriptome analyses suggested that the composition of the tumor microenvironment (TME) corresponds to genetic and clinical features. In this review, we highlight novel findings on the intratumoral heterogeneity of IDH-wildtype and IDH-mutant gliomas characterized at single-cell resolution, and emphasize the mechanisms shaping the immune TME and therapeutic implications.

Recent findings: Emergent evidence indicates that in addition to genetic drivers, epigenetic mechanisms and microenvironmental factors influence the glioma subtypes. Interactions between glioma and immune cells contribute to immune evasion, particularly in aggressive tumors. Spatial and temporal heterogeneity of malignant and immune cell subpopulations is high in recurrent gliomas. IDH-wildtype and IDH-mutant tumors display distinctive changes in their myeloid and lymphoid compartments, and D-2HG produced by IDH-mutant cells impacts the immune TME.

Summary: The comprehensive dissection of the intratumoral ecosystem of human gliomas using single-cell and spatial transcriptomic approaches advances our understanding of the mechanisms underlying the immunosuppressed state of the TME, supports the prognostic value of tumor-associated macrophages and microglial cells, and sheds light on novel therapeutic options.

Box 1

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FIGURE 1

Adult-type diffuse glioma classification (WHO CNS5). The main genetic alterations of IDH-wildtype and IDH-mutant tumors and their corresponding histological appearance are indicated. IDH, isocitrate dehydrogenase.

FIGURE 2

Intratumoral heterogeneity of glioma cells and immune-evasion mechanisms in the mesenchymal-like subtype. (a) The four cellular archetypes present in a given glioma, and their corresponding genetic drivers are indicated. Additional factors influencing the proportion of the MES-like state such as chromosome instability (CIN), hypoxia, irradiation, and a senescent environment are also indicated. (b) Induction of MES-like glioma cells by MES-like macrophages. MES, mesenchymal-like.

FIGURE 3

Effects of the IDH1/2 mutation. Enzymatic activity of IDH-wildtype produces α-ketoglutarate, whereas neomorphic IDH1/2 mutations produce D-2-hydroxyglutarate (D-2HG). Canonical examples of α-ketoglutarate-dependent enzymes and consequences of their inhibition by high levels of D-2HG are also indicated. IDH, isocitrate dehydrogenase.

FIGURE 4

Cellular uptake of D-2-hydroxyglutarate. Cell types able to take up D-2HG according to in-vitro studies as well as two of the transporters so far reported are indicated. D-2HG, D-2-hydroxyglutarate.