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

Nat Commun. 2022 Feb 17;13(1):925. doi: 10.1038/s41467-022-28523-1.


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.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / immunology*
  • Brain Neoplasms / pathology
  • Cell Communication / immunology
  • Cell Line, Tumor
  • Female
  • Glioblastoma / drug therapy
  • Glioblastoma / immunology*
  • Glioblastoma / pathology
  • Healthy Volunteers
  • Heme Oxygenase-1 / metabolism
  • Humans
  • Immunotherapy / methods
  • Interleukin-10 / metabolism*
  • Janus Kinase Inhibitors / pharmacology
  • Janus Kinase Inhibitors / therapeutic use
  • Janus Kinases / antagonists & inhibitors
  • Janus Kinases / metabolism
  • Male
  • Middle Aged
  • Myeloid Cells / metabolism*
  • Neocortex / cytology
  • Neocortex / immunology
  • Neocortex / pathology
  • Primary Cell Culture
  • RNA-Seq
  • STAT Transcription Factors / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Single-Cell Analysis
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Tissue Culture Techniques
  • Tumor Escape
  • Tumor Microenvironment / immunology


  • IL10 protein, human
  • Janus Kinase Inhibitors
  • STAT Transcription Factors
  • Interleukin-10
  • HMOX1 protein, human
  • Heme Oxygenase-1
  • Janus Kinases