Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas
| Autor: | Philipp C. Münch, Lukas Bunse, Camila Fernández-Zapata, Josef Priller, Oliver Schnell, Sabine Heiland, Jürgen Beck, Edward W. Green, Chotima Böttcher, Denis Abu-Sammour, Francisco J. Quintana, Roman Sankowski, Felix Sahm, Carina Ramallo Guevara, Wolfgang Wick, Khwab Sanghvi, Tobias Kessler, Tim Trobisch, Frederik Cichon, Carsten Hopf, Lucas Schirmer, Michael Platten, Dieter Henrik Heiland, Miriam Ratliff, Anna von Landenberg, Theresa Bunse, Jana K. Sonner, Daniel Schrimpf, Mirco Friedrich, Marco Prinz, Hagen M. Gegner, Ilona Gutcher, Stefan Pusch, Michael Kilian, Gernot Poschet, Katrin Aslan, Markus Hahn, Andreas von Deimling |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
genetics [Glioma] Cancer Research Myeloid medicine.medical_treatment genetics [Isocitrate Dehydrogenase] 03 medical and health sciences 0302 clinical medicine Glioma Tumor Microenvironment medicine Bystander effect Humans ddc:610 therapeutic use [Tryptophan] biology Brain Neoplasms Tryptophan Immunotherapy genetics [Tumor Microenvironment] Aryl hydrocarbon receptor medicine.disease Phenotype Isocitrate Dehydrogenase genetics [Brain Neoplasms] 030104 developmental biology medicine.anatomical_structure Isocitrate dehydrogenase Oncology Tumor progression biology.protein Cancer research 030217 neurology & neurosurgery |
| Zdroj: | Nature cancer 2(7), 723-740 (2021). doi:10.1038/s43018-021-00201-z |
| ISSN: | 2662-1347 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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