Abstract
The dynamics and phenotypes of intratumoral myeloid cells during tumor progression are poorly understood. Here we define myeloid cellular states in gliomas by longitudinal single-cell profiling and demonstrate their strict control by the tumor genotype: in isocitrate dehydrogenase (IDH)-mutant tumors, differentiation of infiltrating myeloid cells is blocked, resulting in an immature phenotype. In late-stage gliomas, monocyte-derived macrophages drive tolerogenic alignment of the microenvironment, thus preventing T cell response. We define the IDH-dependent tumor education of infiltrating macrophages to be causally related to a complex re-orchestration of tryptophan metabolism, resulting in activation of the aryl hydrocarbon receptor. We further show that the altered metabolism of IDH-mutant gliomas maintains this axis in bystander cells and that pharmacological inhibition of tryptophan metabolism can reverse immunosuppression. In conclusion, we provide evidence of a glioma genotype-dependent intratumoral network of resident and recruited myeloid cells and identify tryptophan metabolism as a target for immunotherapy of IDH-mutant tumors.
Highlights
The glioma microenvironment orchestrates tumor evolution, progression and resistance to therapy[1]
Current concepts propose a recruitment of blood-borne macrophages to the glioma microenvironment, in which phenotypic and functional shaping of invading macrophages and resident microglia is dependent on the tumor genotype, such as disease-defining mutations in the gene encoding isocitrate dehydrogenase (IDH) type 1 (IDH1) that are causally related to profound tumor cell-intrinsic epigenetic and metabolic alterations associated with a favorable prognosis of patients with glioma[2]
Using hypergeometric tests for enrichments that considered different numbers of cells per condition, we found that myeloid cell clusters (C) C0, C3, C4 and C6 were enriched in cells from control tissues, while C1 and C5 were enriched in cells from IDH-WT high-grade gliomas (HGG), and C2 was enriched in cells from IDH-mutant HGG (Fig. 1d and Extended Data Fig. 1a)
Summary
The glioma microenvironment orchestrates tumor evolution, progression and resistance to therapy[1]. Current concepts propose a recruitment of blood-borne macrophages to the glioma microenvironment, in which phenotypic and functional shaping of invading macrophages and resident microglia is dependent on the tumor genotype, such as disease-defining mutations in the gene encoding IDH type 1 (IDH1) that are causally related to profound tumor cell-intrinsic epigenetic and metabolic alterations associated with a favorable prognosis of patients with glioma[2]. While studies to date suggest a continuum rather than a bimodal distribution of microglia-specific versus macrophage-specific genes in myeloid cells[3], temporal cell type-specific functional states within the glioma microenvironment have not been defined. Such analyses would reveal important molecular determinants of functional. We comprehensively define longitudinal homeostatic and antigen-presenting myeloid cellular states, assess their tumor-genotype dependence and reveal underlying metabolic mechanisms controlling them
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