PMID- 35177622 OWN - NLM STAT- MEDLINE VI - 13 IP - 1 TI - T-cell dysfunction in the glioblastoma microenvironment is mediated by myeloid cells releasing interleukin-10. PG - 925 CI - © 2022. The Author(s). LA - eng PT - Journal Article PT - Observational Study PT - Research Support, Non-U.S. Gov't PL - England TA - Nat Commun JT - Nature communications JID - 101528555 IS - 2041-1723 (Electronic) LID - 10.1038/s41467-022-28523-1 [doi] FAU - Ravi, Vidhya M AU - Ravi VM AUID- ORCID: http://orcid.org/0000-0003-0062-2099 AD - Microenvironment and Immunology Research Laboratory, Medical Center-University of Freiburg, Freiburg, Germany. AD - Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany. AD - Faculty of Medicine, University of Freiburg, Freiburg, Germany. AD - Neuroelectronic Systems, Medical Center-University of Freiburg, Freiburg, Germany. AD - Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Freiburg, Germany. FAU - Neidert, Nicolas AU - Neidert N AUID- ORCID: http://orcid.org/0000-0003-0299-1138 AD - Microenvironment and Immunology Research Laboratory, Medical Center-University of Freiburg, Freiburg, Germany. AD - Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany. AD - Faculty of Medicine, University of Freiburg, Freiburg, Germany. AD - Translational NeuroOncology Research Group, Medical Center-University of Freiburg, Freiburg, Germany. FAU - Will, Paulina AU - Will P AUID- ORCID: http://orcid.org/0000-0001-5924-2432 AD - Microenvironment and Immunology Research Laboratory, Medical Center-University of Freiburg, Freiburg, Germany. AD - Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany. AD - Faculty of Medicine, University of Freiburg, Freiburg, Germany. FAU - Joseph, Kevin AU - Joseph K AUID- ORCID: http://orcid.org/0000-0001-6317-8736 AD - Microenvironment and Immunology Research Laboratory, Medical Center-University of Freiburg, Freiburg, Germany. AD - Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany. AD - Faculty of Medicine, University of Freiburg, Freiburg, Germany. FAU - Maier, Julian P AU - Maier JP AUID- ORCID: http://orcid.org/0000-0002-2957-9031 AD - Microenvironment and Immunology Research Laboratory, Medical Center-University of Freiburg, Freiburg, Germany. AD - Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany. AD - Faculty of Medicine, University of Freiburg, Freiburg, Germany. FAU - Kückelhaus, Jan AU - Kückelhaus J AD - Microenvironment and Immunology Research Laboratory, Medical Center-University of Freiburg, Freiburg, Germany. AD - Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany. AD - Faculty of Medicine, University of Freiburg, Freiburg, Germany. FAU - Vollmer, Lea AU - Vollmer L AD - Microenvironment and Immunology Research Laboratory, Medical Center-University of Freiburg, Freiburg, Germany. AD - Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany. AD - Faculty of Medicine, University of Freiburg, Freiburg, Germany. FAU - Goeldner, Jonathan M AU - Goeldner JM AUID- ORCID: http://orcid.org/0000-0003-2394-7312 AD - Microenvironment and Immunology Research Laboratory, Medical Center-University of Freiburg, Freiburg, Germany. AD - Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany. AD - Faculty of Medicine, University of Freiburg, Freiburg, Germany. FAU - Behringer, Simon P AU - Behringer SP AD - Microenvironment and Immunology Research Laboratory, Medical Center-University of Freiburg, Freiburg, Germany. AD - Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany. AD - Faculty of Medicine, University of Freiburg, Freiburg, Germany. AD - Translational NeuroOncology Research Group, Medical Center-University of Freiburg, Freiburg, Germany. FAU - Scherer, Florian AU - Scherer F AUID- ORCID: http://orcid.org/0000-0001-9635-5487 AD - Faculty of Medicine, University of Freiburg, Freiburg, Germany. AD - Department of Medicine I, Medical Center-University of Freiburg, Freiburg, Germany. FAU - Boerries, Melanie AU - Boerries M AD - Faculty of Medicine, University of Freiburg, Freiburg, Germany. AD - Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg, Freiburg, Germany. AD - Comprehensive Cancer Center Freiburg (CCCF), Faculty of Medicine and Medical Center-University of Freiburg, Freiburg, Germany. AD - German Cancer Consortium (DKTK), partner site Freiburg, Freiburg, Germany. FAU - Follo, Marie AU - Follo M AD - Faculty of Medicine, University of Freiburg, Freiburg, Germany. AD - Department of Medicine I, Medical Center-University of Freiburg, Freiburg, Germany. FAU - Weiss, Tobias AU - Weiss T AUID- ORCID: http://orcid.org/0000-0002-5533-9429 AD - Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland. FAU - Delev, Daniel AU - Delev D AD - Department of Neurosurgery, RWTH University of Aachen, Aachen, Germany. AD - Neurosurgical Artificial Intelligence Laboratory Aachen (NAILA), Department of Neurosurgery, RWTH University of Aachen, Aachen, Germany. FAU - Kernbach, Julius AU - Kernbach J AUID- ORCID: http://orcid.org/0000-0002-0256-1923 AD - Department of Neurosurgery, RWTH University of Aachen, Aachen, Germany. AD - Neurosurgical Artificial Intelligence Laboratory Aachen (NAILA), Department of Neurosurgery, RWTH University of Aachen, Aachen, Germany. FAU - Franco, Pamela AU - Franco P AD - Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany. AD - Faculty of Medicine, University of Freiburg, Freiburg, Germany. AD - Translational NeuroOncology Research Group, Medical Center-University of Freiburg, Freiburg, Germany. FAU - Schallner, Nils AU - Schallner N AD - Faculty of Medicine, University of Freiburg, Freiburg, Germany. AD - Department of Anesthesiology and Critical Care Medicine, Medical Center-University of Freiburg, Freiburg, Germany. FAU - Dierks, Christine AU - Dierks C AD - Faculty of Medicine, University of Freiburg, Freiburg, Germany. AD - Department of Medicine I, Medical Center-University of Freiburg, Freiburg, Germany. FAU - Carro, Maria Stella AU - Carro MS AUID- ORCID: http://orcid.org/0000-0002-8570-7691 AD - Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany. AD - Faculty of Medicine, University of Freiburg, Freiburg, Germany. FAU - Hofmann, Ulrich G AU - Hofmann UG AD - Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany. AD - Faculty of Medicine, University of Freiburg, Freiburg, Germany. AD - Neuroelectronic Systems, Medical Center-University of Freiburg, Freiburg, Germany. FAU - Fung, Christian AU - Fung C AD - Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany. AD - Faculty of Medicine, University of Freiburg, Freiburg, Germany. FAU - Sankowski, Roman AU - Sankowski R AUID- ORCID: http://orcid.org/0000-0001-9215-8021 AD - Faculty of Medicine, University of Freiburg, Freiburg, Germany. AD - Institute of Neuropathology, Medical Center-University of Freiburg, Freiburg, Germany. FAU - Prinz, Marco AU - Prinz M AUID- ORCID: http://orcid.org/0000-0002-0349-1955 AD - Faculty of Medicine, University of Freiburg, Freiburg, Germany. AD - Institute of Neuropathology, Medical Center-University of Freiburg, Freiburg, Germany. AD - Signalling Research Centre BIOSS and CIBSS, University of Freiburg, Freiburg, Germany. AD - Center for NeuroModulation (NeuroModul), University of Freiburg, Freiburg, Germany. FAU - Beck, Jürgen AU - Beck J AD - Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany. AD - Faculty of Medicine, University of Freiburg, Freiburg, Germany. AD - Center for NeuroModulation (NeuroModul), University of Freiburg, Freiburg, Germany. FAU - Salié, Henrike AU - Salié H AUID- ORCID: http://orcid.org/0000-0002-2993-3782 AD - Faculty of Medicine, University of Freiburg, Freiburg, Germany. AD - Signalling Research Centre BIOSS and CIBSS, University of Freiburg, Freiburg, Germany. AD - Department of Medicine II: Gastroenterology, Hepatology, Endocrinology, and Infectious Disease, Medical Center- University of Freiburg, Freiburg, Germany. FAU - Bengsch, Bertram AU - Bengsch B AUID- ORCID: http://orcid.org/0000-0003-2552-740X AD - Faculty of Medicine, University of Freiburg, Freiburg, Germany. AD - Signalling Research Centre BIOSS and CIBSS, University of Freiburg, Freiburg, Germany. AD - Department of Medicine II: Gastroenterology, Hepatology, Endocrinology, and Infectious Disease, Medical Center- University of Freiburg, Freiburg, Germany. FAU - Schnell, Oliver AU - Schnell O AD - Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany. AD - Faculty of Medicine, University of Freiburg, Freiburg, Germany. AD - Translational NeuroOncology Research Group, Medical Center-University of Freiburg, Freiburg, Germany. FAU - Heiland, Dieter Henrik AU - Heiland DH AUID- ORCID: http://orcid.org/0000-0002-9258-3033 AD - Microenvironment and Immunology Research Laboratory, Medical Center-University of Freiburg, Freiburg, Germany. dieter.henrik.heiland@uniklinik-freiburg.de. AD - Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany. dieter.henrik.heiland@uniklinik-freiburg.de. AD - Faculty of Medicine, University of Freiburg, Freiburg, Germany. dieter.henrik.heiland@uniklinik-freiburg.de. AD - Comprehensive Cancer Center Freiburg (CCCF), Faculty of Medicine and Medical Center-University of Freiburg, Freiburg, Germany. dieter.henrik.heiland@uniklinik-freiburg.de. AD - German Cancer Consortium (DKTK), partner site Freiburg, Freiburg, Germany. dieter.henrik.heiland@uniklinik-freiburg.de. IS - 2041-1723 (Linking) RN - 0 (IL10 protein, human) RN - 0 (Janus Kinase Inhibitors) RN - 0 (STAT Transcription Factors) RN - 130068-27-8 (Interleukin-10) RN - EC 1.14.14.18 (HMOX1 protein, human) RN - EC 1.14.14.18 (Heme Oxygenase-1) RN - EC 2.7.10.2 (Janus Kinases) SB - IM MH - Adult MH - Aged MH - Brain Neoplasms/drug therapy/*immunology/pathology MH - Cell Communication/immunology MH - Cell Line, Tumor MH - Female MH - Glioblastoma/drug therapy/*immunology/pathology MH - Healthy Volunteers MH - Heme Oxygenase-1/metabolism MH - Humans MH - Immunotherapy/methods MH - Interleukin-10/*metabolism MH - Janus Kinase Inhibitors/pharmacology/therapeutic use MH - Janus Kinases/antagonists & inhibitors/metabolism MH - Male MH - Middle Aged MH - Myeloid Cells/*metabolism MH - Neocortex/cytology/immunology/pathology MH - Primary Cell Culture MH - RNA-Seq MH - STAT Transcription Factors/metabolism MH - Signal Transduction/drug effects/immunology MH - Single-Cell Analysis MH - T-Lymphocytes/drug effects/*immunology/metabolism MH - Tissue Culture Techniques MH - Tumor Escape MH - Tumor Microenvironment/immunology PMC - PMC8854421 DCOM- 20220303 LR - 20221109 DP - 20220217 DEP - 20220217 AB - Despite recent advances in cancer immunotherapy, certain tumor types, such as Glioblastomas, are highly resistant due to their tumor microenvironment disabling the anti-tumor immune response. Here we show, by applying an in-silico multidimensional model integrating spatially resolved and single-cell gene expression data of 45,615 immune cells from 12 tumor samples, that a subset of Interleukin-10-releasing HMOX1+ myeloid cells, spatially localizing to mesenchymal-like tumor regions, drive T-cell exhaustion and thus contribute to the immunosuppressive tumor microenvironment. These findings are validated using a human ex-vivo neocortical glioblastoma model inoculated with patient derived peripheral T-cells to simulate the immune compartment. This model recapitulates the dysfunctional transformation of tumor infiltrating T-cells. Inhibition of the JAK/STAT pathway rescues T-cell functionality both in our model and in-vivo, providing further evidence of IL-10 release being an important driving force of tumor immune escape. Our results thus show that integrative modelling of single cell and spatial transcriptomics data is a valuable tool to interrogate the tumor immune microenvironment and might contribute to the development of successful immunotherapies.