학술논문
Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas
Document Type
Original Paper
Author
Friedrich, Mirco; Sankowski, Roman; Bunse, Lukas; Kilian, Michael; Green, Edward; Ramallo Guevara, Carina; Pusch, Stefan; Poschet, Gernot; Sanghvi, Khwab; Hahn, Markus; Bunse, Theresa; Münch, Philipp; Gegner, Hagen M.; Sonner, Jana K.; von Landenberg, Anna; Cichon, Frederik; Aslan, Katrin; Trobisch, Tim; Schirmer, Lucas; Abu-Sammour, Denis; Kessler, Tobias; Ratliff, Miriam; Schrimpf, Daniel; Sahm, Felix; Hopf, Carsten; Heiland, Dieter H.; Schnell, Oliver; Beck, Jürgen; Böttcher, Chotima; Fernandez-Zapata, Camila; Priller, Josef; Heiland, Sabine; Gutcher, Ilona; Quintana, Francisco J.; von Deimling, Andreas; Wick, Wolfgang; Prinz, Marco; Platten, Michael
Source
Nature Cancer. 2(7):723-740
Subject
Language
English
ISSN
2662-1347
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.
Platten and colleagues find that tryptophan metabolism by myeloid cells contributes to immunosuppressive microenvironment uniquely in IDH-mutant gliomas, which can be overcome by inhibiting this pathway in murine tumor models.
Platten and colleagues find that tryptophan metabolism by myeloid cells contributes to immunosuppressive microenvironment uniquely in IDH-mutant gliomas, which can be overcome by inhibiting this pathway in murine tumor models.