Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas

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.

Analyzing microglial phenotypes across neuropathologies: a practical guide

“…So far, many CNS pathologies and their respective animal models have been analyzed using single-cell RNA sequencing approaches, e.g. Alzheimer's disease [27,48], Multiple Sclerosis [26,36] or gliomas [12]. Intracerebral macrophages other than microglia, i.e.…”

“…Single-cell technologies have tremendously helped to better understand CAMs/BAMs in health and disease [26,43,73]. Single-cell RNA-sequencing was able to define myeloid cell clusters in isocitrate dehydrogenase (IDH) 1 mutant astrocytomas that were not present in IDH-1 wild-type gliomas, which may have both diagnostic and therapeutic consequences [12].…”

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

“…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 gliomaassociated macrophages (GAMs), opening up new avenues for intervention [5].…”

“…Friedrich and colleagues explored the different immune cell populations present in the TME of human gliomas [5]. 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.…”

“…While Friedrich et al show that IDHmutant gliomas educate their infiltrating macrophages toward an immunosuppressive phenotype [5], the question remains, how do these findings translate to the situation in patients [1]? Although IDH mutations may contribute to tumorigenesis by blocking differentiation of progenitor cells via epigenetic mechanisms [6], they correlate with improved prognosis in established gliomas [1].…”