Glioblastoma cancer stem cells evade innate immune suppression of self-renewal through reduced TLR4 expression

Identification: 2030


Description

Glioblastoma cancer stem cells evade innate immune suppression of self-renewal through reduced TLR4 expression

Alvaro Alvarado1, Erin Mulkearns-Hubert1, Daniel Silver1, Tyler Alban1, Michelle Longworth1, Michael Vogelbaum2, Justin Lathia1,2,*

1Department of Cellular and Molecular Medicine, Lerner Research Institute; 2Rose Ella Burkhardt Brain Tumor Center; Cleveland Clinic, Cleveland, OH

*Corresponding author

The tumor microenvironment presents a unique set of signals to tumor cells that instruct their behavior. While many microenvironmental signals provide a growth and survival advantage, tumors also 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. Using cancer stem cells (CSCs) from glioblastoma patient-derived xenografts, we find that proliferation of non-CSCs is attenuated by TLR ligands, whereas CSC proliferation is unaffected by ligand exposure. Profiling revealed that CSCs have reduced levels of TLR4 compared to non-CSCs and that low TLR4 expression correlates with aggressive disease progression. Overexpression of TLR4 in CSCs reduced stem cell signaling and attenuated proliferation, self-renewal, and tumor growth. Mechanistically, TLR4 signaling is directly connected to the stem cell transcriptional program through tank-binding kinase 1 (TBK1) and retinoblastoma binding protein 5 (RBBP5). Further, RBBP5 is necessary and sufficient for CSC self-renewal via epigenetic regulation of the genes encoding core self-renewal transcription factors. The activation of TBK1 downstream of TLR4 suppresses RBBP5 expression. Our findings reveal a unique pathway through which TLR4 potently suppresses the stem cell state, linking innate immune signaling responses to stem cell maintenance. These findings provide a mechanism through which CSCs persist in hostile environments due to an inability to respond to inflammatory signals.

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