The cancer stem cell subtype determines immune infiltration of glioblastoma.
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.
Department of Neurology, RWTH Aachen, Aachen, Germany.
Christoph P
CP
Beier
Praveen
P
Kumar
Katharina
K
Meyer
Petra
P
Leukel
Valentin
V
Bruttel
Ines
I
Aschenbrenner
Markus J
MJ
Riemenschneider
Athanassios
A
Fragoulis
Petra
P
Rümmele
Katrin
K
Lamszus
Jörg B
JB
Schulz
Joachim
J
Weis
Ulrich
U
Bogdahn
Jörg
J
Wischhusen
Peter
P
Hau
Rainer
R
Spang
Dagmar
D
Beier
D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007155:Immunologic Factors / Q000502:physiology; D051379:Mice; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000378:metabolism; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000276:immunology* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051899:Smad2 Protein / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000473:pathology; D015533:Transcriptional Activation; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000502:physiology; D047368:Tumor Burden / Q000276:immunology
D007155:Immunologic Factors; D055655:NK Cell Lectin-Like Receptor Subfamily K; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta