Primary cilia modulate extracellular vesicle-mediated immunosuppression in human glioblastoma cells

Authors

• KA Maki
• JJ Barb
• LY Hsu
• L Yang
• VA Ramchandani
• ML Schwandt
• N Diazgranados
• R Momenan
• GR Wallen

Abstract

Glioblastoma is the most common malignant primary brain tumor. Median survival is 15 months despite surgery, radiation, and chemotherapy. The disease is universally fatal with 5-years survival only 3-5%. Immunotherapy is promising but glioblastoma-mediated immunosuppression remains a barrier. Extracellular vesicles (EVs) comprise a heterogeneous group of small, membrane-bound particles released from all cell types. Tumor-derived EVs induce immunosuppressive myeloid-derived suppressor cells (MDSCs) which in turn inhibit T-cell proliferation and activation. This appears to be a pan-cancer phenomenon which is also active in glioblastomas.
Primary cilia are ubiquitous microtubule-based organelles that project from the mother centriole. They are present on glioblastomas and multiple additional cancer cells. We provide evidence that inhibition of glioblastoma ciliogenesis through genetic depletion of KIF3A, IFT88, or ARL13B–structural ciliary proteins necessary for ciliogenesis–reduces MDSCs induction following exposure of normal human monocytes to glioblastoma-derived EVs. Loss of primary cilia also rescues impairment of T-cell proliferation and activation. Biophysical characterization of EVs derived from glioblastoma cells are unchanged following cilia loss. However, LC-MS proteome analysis confirms profound changes in EV content including upregulation of genes and pathways involved in tumor cell death and downregulation of genes and pathways involved in tumor immune regulation. These data suggest a novel role for primary cilia in modulating glioblastoma-mediated immunosuppression and likely, cancer-mediated immunosuppression more broadly. These findings have potential implication for improving the efficacy of immunotherapy in glioblastoma, a universally fatal disease for which this class of therapy remains ineffective.

Scientific Focus Area: Cancer Biology

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