Glioblastoma Cancer Stem Cells Evade Innate Immune Suppression of Self-Renewal through Reduced TLR4 Expression

Publication date: Available online 12 January 2017
Source:Cell Stem Cell
Author(s): Alvaro G. Alvarado, Praveena S. Thiagarajan, Erin E. Mulkearns-Hubert, Daniel J. Silver, James S. Hale, Tyler J. Alban, Soumya M. Turaga, Awad Jarrar, Ofer Reizes, Michelle S. Longworth, Michael A. Vogelbaum, Justin D. Lathia
Tumors contain hostile inflammatory signals generated by aberrant proliferation, necrosis, and hypoxia. These signals are sensed and acted upon acutely by the Toll-like receptors (TLRs) to halt proliferation and activate an immune response. Despite the presence of TLR ligands within the microenvironment, tumors progress, and the mechanisms that permit this growth remain largely unknown. We report that self-renewing cancer stem cells (CSCs) in glioblastoma have low TLR4 expression that allows them to survive by disregarding inflammatory signals. Non-CSCs express high levels of TLR4 and respond to ligands. TLR4 signaling suppresses CSC properties by reducing retinoblastoma binding protein 5 (RBBP5), which is elevated in CSCs. RBBP5 activates core stem cell transcription factors, is necessary and sufficient for self-renewal, and is suppressed by TLR4 overexpression in CSCs. Our findings provide a mechanism through which CSCs persist in hostile environments because of an inability to respond to inflammatory signals.

Graphical abstract

Teaser

Alvarado et al. demonstrate that glioblastoma cancer stem cells express a lower level of the innate immune receptor TLR4 than surrounding cells, which allows them to avoid inhibitory innate immune signaling that would otherwise suppress self-renewal.


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