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

Mirco Friedrich, Roman Sankowski, Lukas Bunse, Michael Kilian, Edward Green, Carina Ramallo Guevara, Stefan Pusch, Gernot Poschet, Khwab Sanghvi, Markus Hahn, Theresa Bunse, Philipp Münch, Hagen M. Gegner, Jana K. Sonner, Anna von Landenberg, Frederik Cichon, Katrin Aslan, Tim Trobisch, Lucas Schirmer, Denis Abu-SammourTobias Kessler, Miriam Ratliff, Daniel Schrimpf, Felix Sahm, Carsten Hopf, Dieter H. Heiland, Oliver Schnell, Jürgen Beck, Chotima Böttcher, Camila Fernandez-Zapata, Josef Priller, Sabine Heiland, Ilona Gutcher, Francisco J. Quintana, Andreas von Deimling, Wolfgang Wick, Marco Prinz, Michael Platten

Research output: Contribution to journalArticlepeer-review

112 Scopus citations

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.

Original languageEnglish
Pages (from-to)723-740
Number of pages18
JournalNature Cancer
Volume2
Issue number7
DOIs
StatePublished - Jul 2021
Externally publishedYes

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