T-cell dysfunction in the glioblastoma microenvironment is mediated by myeloid cells releasing interleukin-10.

Julius Kernbach, Dieter Henrik Heiland, Oliver Schnell, Bertram Bengsch, Henrike Salié, Jürgen Beck, Marco Prinz, Roman Sankowski, Christian Fung, Ulrich G Hofmann, Maria Stella Carro, Christine Dierks, Nils Schallner, Pamela Franco, Vidhya M Ravi, Daniel Delev, Tobias Weiss, Marie Follo, Melanie Boerries, Florian Scherer, Simon P Behringer, Jonathan M Goeldner, Lea Vollmer, Jan Kückelhaus, Julian P Maier, Kevin Joseph, Paulina Will, Nicolas Neidert

Journal: Nature communications 2022;13(1):925

PMID: 35177622

Free Full Text on Nature Publishing Group View on PubMed

Abstract

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.

Address: Microenvironment and Immunology Research Laboratory, Medical Center-University of Freiburg, Freiburg, Germany.; Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany.; Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Neuroelectronic Systems, Medical Center-University of Freiburg, Freiburg, Germany.; Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Freiburg, Germany.; Translational NeuroOncology Research Group, Medical Center-University of Freiburg, Freiburg, Germany.; Department of Medicine I, Medical Center-University of Freiburg, Freiburg, Germany.; Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg, Freiburg, Germany.; Comprehensive Cancer Center Freiburg (CCCF), Faculty of Medicine and Medical Center-University of Freiburg, Freiburg, Germany.; German Cancer Consortium (DKTK), partner site Freiburg, Freiburg, Germany.; Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland.; Department of Neurosurgery, RWTH University of Aachen, Aachen, Germany.; Neurosurgical Artificial Intelligence Laboratory Aachen (NAILA), Department of Neurosurgery, RWTH University of Aachen, Aachen, Germany.; Department of Anesthesiology and Critical Care Medicine, Medical Center-University of Freiburg, Freiburg, Germany.; Institute of Neuropathology, Medical Center-University of Freiburg, Freiburg, Germany.; Signalling Research Centre BIOSS and CIBSS, University of Freiburg, Freiburg, Germany.; Center for NeuroModulation (NeuroModul), University of Freiburg, Freiburg, Germany.; Department of Medicine II: Gastroenterology, Hepatology, Endocrinology, and Infectious Disease, Medical Center- University of Freiburg, Freiburg, Germany.; Microenvironment and Immunology Research Laboratory, Medical Center-University of Freiburg, Freiburg, Germany. [email protected].; Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany. [email protected].; Faculty of Medicine, University of Freiburg, Freiburg, Germany. [email protected].; Comprehensive Cancer Center Freiburg (CCCF), Faculty of Medicine and Medical Center-University of Freiburg, Freiburg, Germany. [email protected].; German Cancer Consortium (DKTK), partner site Freiburg, Freiburg, Germany. [email protected].

DOI: 10.1038/s41467-022-28523-1

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MeSH Terms: Adult, Aged, Brain Neoplasms, Cell Communication, Cell Line, Tumor, Female, Glioblastoma, Healthy Volunteers, Heme Oxygenase-1, Humans, Immunotherapy, Interleukin-10, Janus Kinase Inhibitors, Janus Kinases, Male, Middle Aged, Myeloid Cells, Neocortex, Primary Cell Culture, RNA-Seq, STAT Transcription Factors, Signal Transduction, Single-Cell Analysis, T-Lymphocytes, Tissue Culture Techniques, Tumor Escape, Tumor Microenvironment