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.

• Authors: 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-Sammour, Tobias 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
• Journal: Nature cancer (Nat Cancer) Vol. 2 Issue 7 Pg. 723-740 (07 2021) ISSN: 2662-1347 [Electronic] England
• PMID: 35121943 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Tryptophan
• Isocitrate Dehydrogenase

Topics

• Brain Neoplasms (genetics)
• Glioma (genetics)
• Humans
• Immunotherapy
• Isocitrate Dehydrogenase (genetics)
• Tryptophan (therapeutic use)
• Tumor Microenvironment (genetics)