Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas.

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     «

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-...     »

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.      «

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...     »