Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas
Open Access
- 24 May 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Cancer
- Vol. 2 (7), 723-740
- https://doi.org/10.1038/s43018-021-00201-z
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.Keywords
Funding Information
- Deutsche Krebshilfe
- Deutsche Forschungsgemeinschaft
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