TY  - JOUR
AU  - Friedrich, Mirco
AU  - Sankowski, Roman
AU  - Bunse, Lukas
AU  - Kilian, Michael
AU  - Green, Edward
AU  - Ramallo Guevara, Carina
AU  - Pusch, Stefan
AU  - Poschet, Gernot
AU  - Sanghvi, Khwab
AU  - Hahn, Markus
AU  - Bunse, Theresa
AU  - Münch, Philipp
AU  - Gegner, Hagen M.
AU  - Sonner, Jana K.
AU  - von Landenberg, Anna
AU  - Cichon, Frederik
AU  - Aslan, Katrin
AU  - Trobisch, Tim
AU  - Schirmer, Lucas
AU  - Abu-Sammour, Denis
AU  - Kessler, Tobias
AU  - Ratliff, Miriam
AU  - Schrimpf, Daniel
AU  - Sahm, Felix
AU  - Hopf, Carsten
AU  - Heiland, Dieter H.
AU  - Schnell, Oliver
AU  - Beck, Jürgen
AU  - Böttcher, Chotima
AU  - Fernandez-Zapata, Camila
AU  - Priller, Josef
AU  - Heiland, Sabine
AU  - Gutcher, Ilona
AU  - Quintana, Francisco J.
AU  - von Deimling, Andreas
AU  - Wick, Wolfgang
AU  - Prinz, Marco
AU  - Platten, Michael
TI  - Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas
JO  - Nature cancer
VL  - 2
IS  - 7
SN  - 2662-1347
CY  - London
PB  - Nature Research
M1  - DZNE-2021-00742
SP  - 723 - 740
PY  - 2021
AB  - 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.
KW  - Brain Neoplasms: genetics
KW  - Glioma: genetics
KW  - Humans
KW  - Immunotherapy
KW  - Isocitrate Dehydrogenase: genetics
KW  - Tryptophan: therapeutic use
KW  - Tumor Microenvironment: genetics
KW  - Tryptophan (NLM Chemicals)
KW  - Isocitrate Dehydrogenase (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:35121943
DO  - DOI:10.1038/s43018-021-00201-z
UR  - https://pub.dzne.de/record/155564
ER  -