Journal Article

DZNE-2021-00742

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png 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, H. M. ; Sonner, J. K. ; 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, D. H. ; Schnell, O. ; Beck, J. ; Böttcher, C.Extern* ; Fernandez-Zapata, C. ; Priller, J.DZNE* ; Heiland, S. ; Gutcher, I. ; Quintana, F. J. ; von Deimling, A. ; Wick, W. ; Prinz, M. ; Platten, M. (Corresponding author)

2021
Nature Research London

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Please use a persistent id in citations: 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.

Keyword(s): Brain Neoplasms: genetics (MeSH) ; Glioma: genetics (MeSH) ; Humans (MeSH) ; Immunotherapy (MeSH) ; Isocitrate Dehydrogenase: genetics (MeSH) ; Tryptophan: therapeutic use (MeSH) ; Tumor Microenvironment: genetics (MeSH) ; Tryptophan ; Isocitrate Dehydrogenase

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Contributing Institute(s):

1. Clinical Study Team Berlin Priller (Clinical Study Team Berlin 1 ; AG Priller)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2021

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; DEAL Nature ; Essential Science Indicators ; IF >= 20 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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