Interactions between cancer cells and immune cells drive transitions to mesenchymal-like states in glioblastoma

Cancer Cell. 2021 Jun 14;39(6):779-792.e11. doi: 10.1016/j.ccell.2021.05.002. Epub 2021 Jun 3.

Abstract

The mesenchymal subtype of glioblastoma is thought to be determined by both cancer cell-intrinsic alterations and extrinsic cellular interactions, but remains poorly understood. Here, we dissect glioblastoma-to-microenvironment interactions by single-cell RNA sequencing analysis of human tumors and model systems, combined with functional experiments. We demonstrate that macrophages induce a transition of glioblastoma cells into mesenchymal-like (MES-like) states. This effect is mediated, both in vitro and in vivo, by macrophage-derived oncostatin M (OSM) that interacts with its receptors (OSMR or LIFR) in complex with GP130 on glioblastoma cells and activates STAT3. We show that MES-like glioblastoma states are also associated with increased expression of a mesenchymal program in macrophages and with increased cytotoxicity of T cells, highlighting extensive alterations of the immune microenvironment with potential therapeutic implications.

Keywords: GBM; OSM; glioblastoma; macrophage; mesenchymal; scRNA-seq; tumor microenvironment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Neoplasms / genetics
  • Brain Neoplasms / immunology*
  • Brain Neoplasms / pathology*
  • Cells, Cultured
  • Cytokine Receptor gp130 / genetics
  • Cytokine Receptor gp130 / metabolism
  • Cytotoxicity, Immunologic
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma / genetics
  • Glioblastoma / immunology*
  • Glioblastoma / pathology*
  • Humans
  • Leukemia Inhibitory Factor Receptor alpha Subunit / genetics
  • Leukemia Inhibitory Factor Receptor alpha Subunit / metabolism
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Oncostatin M / metabolism
  • Oncostatin M Receptor beta Subunit / genetics
  • Oncostatin M Receptor beta Subunit / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • T-Lymphocytes / immunology*
  • Tumor Microenvironment
  • Tumor-Associated Macrophages / immunology*
  • Tumor-Associated Macrophages / pathology

Substances

  • IL6ST protein, human
  • LIFR protein, human
  • Leukemia Inhibitory Factor Receptor alpha Subunit
  • OSMR protein, human
  • Oncostatin M Receptor beta Subunit
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Oncostatin M
  • Cytokine Receptor gp130