Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas
Friedrich M, Sankowski R, Bunse L, Kilian M, Green E, Ramallo Guevara C, Pusch S, Poschet G, Sanghvi K, Hahn M, Bunse T, Münch P, Gegner HM, Sonner JK, von Landenberg A, Cichon F, Aslan K, Trobisch T, Schirmer L, Abu-Sammour D, Kessler T, Ratliff M, Schrimpf D, Sahm F, Hopf C, Heiland DH, Schnell O, Beck J, Böttcher C, Fernandez-Zapata C, Priller J, Heiland S, Gutcher I, Quintana FJ, von Deimling A, Wick W, Prinz M, Platten M (2021)
Publication Type: Journal article
Publication year: 2021
Journal
Book Volume: 2
Pages Range: 723-740
Journal Issue: 7
DOI: 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.
Authors with CRIS profile
Involved external institutions
Universitätsklinikum Freiburg
Germany (DE)
Deutsches Krebsforschungszentrum (DKFZ)
Germany (DE)
Albert-Ludwigs-Universität Freiburg
Germany (DE)
Universitätsklinikum Heidelberg
Germany (DE)
Ruprecht-Karls-Universität Heidelberg
Germany (DE)
Hochschule Mannheim University of Applied Sciences
Germany (DE)
Universitätsklinikum Mannheim
Germany (DE)
Charité - Universitätsmedizin Berlin
Germany (DE)
Bayer HealthCare AG
Germany (DE)
Brigham and Women's Hospital (BWH)
United States (USA) (US)
Germany (DE)
Deutsches Krebsforschungszentrum (DKFZ)
Germany (DE)
Albert-Ludwigs-Universität Freiburg
Germany (DE)
Universitätsklinikum Heidelberg
Germany (DE)
Ruprecht-Karls-Universität Heidelberg
Germany (DE)
Hochschule Mannheim University of Applied Sciences
Germany (DE)
Universitätsklinikum Mannheim
Germany (DE)
Charité - Universitätsmedizin Berlin
Germany (DE)
Bayer HealthCare AG
Germany (DE)
Brigham and Women's Hospital (BWH)
United States (USA) (US)
How to cite
APA:
Friedrich, M., Sankowski, R., Bunse, L., Kilian, M., Green, E., Ramallo Guevara, C.,... Platten, M. (2021). Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas. Nature Cancer, 2(7), 723-740. https://doi.org/10.1038/s43018-021-00201-z
MLA:
Friedrich, Mirco, et al. "Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas." Nature Cancer 2.7 (2021): 723-740.
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