The cancer stem cell subtype determines immune infiltration of glioblastoma

Stem Cells Dev. 2012 Oct 10;21(15):2753-61. doi: 10.1089/scd.2011.0660. Epub 2012 Jul 16.


Immune cell infiltration varies widely between different glioblastomas (GBMs). The underlying mechanism, however, remains unknown. Here we show that TGF-beta regulates proliferation, migration, and tumorigenicity of mesenchymal GBM cancer stem cells (CSCs) in vivo and in vitro. In contrast, proneural GBM CSCs resisted TGF-beta due to TGFR2 deficiency. In vivo, a substantially increased infiltration of immune cells was observed in mesenchymal GBMs, while immune infiltrates were rare in proneural GBMs. On a functional level, proneural CSC lines caused a significantly stronger TGF-beta-dependent suppression of NKG2D expression on CD8(+) T and NK cells in vitro providing a mechanistic explanation for the reduced immune infiltration of proneural GBMs. Thus, the molecular subtype of CSCs TGF-beta-dependently contributes to the degree of immune infiltration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Neoplasms / immunology*
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma / immunology*
  • Glioblastoma / pathology
  • Humans
  • Immunologic Factors / physiology
  • Mice
  • NK Cell Lectin-Like Receptor Subfamily K / genetics
  • NK Cell Lectin-Like Receptor Subfamily K / metabolism
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / immunology*
  • Neoplastic Stem Cells / pathology
  • Oligonucleotide Array Sequence Analysis
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Smad2 Protein / metabolism
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / pathology
  • Transcriptional Activation
  • Transcriptome
  • Transforming Growth Factor beta / physiology
  • Tumor Burden / immunology


  • Immunologic Factors
  • NK Cell Lectin-Like Receptor Subfamily K
  • SMAD2 protein, human
  • Smad2 Protein
  • Transforming Growth Factor beta