Abstract
Tumor regression in sites distant to the irradiated field are thought to be associated with emission of damage-associated molecular patterns (DAMPs) molecules and generation of immunogenic cell death (ICD). Glioma stem cells (GSCs) are resistant to high doses of radiation, and ultimately select the outgrowth of a more aggressive tumor. This study showed high-dose IR triggered fewer DAMPs molecules exposure and release in GSCs comparing to matched non-GSCs. Downregulation of binding immunoglobulin protein (Bip) promoted IR-mediated endoplasmic reticulum stress to generate DAMPs molecules by PERK and IRE1-α phosphorylation, and increased dendritic cells mature and effector T lymphocytes activation. GSCs treated with Bip knockdown and IR efficiently prevented tumor generation, and reduced post-radiotherapy tumor recurrence. These data suggest that Bip plays a critical role in inhibition of IR-induced ICD in GSCs, and Bip inhibition may be a promising strategy on adjuvant therapy by ameliorating tumor immune microenvironment.
Highlights
Glioblastoma (GBM) is the most aggressive primary brain tumor with a high mortality rate
We found high-dose ionizing radiation (IR) triggered fewer damage-associated molecular patterns (DAMPs) molecules exposure and release comparing to non-glioma stem cells (GSCs), which made the immune response elicited by RT insufficient to eliminate GSCs
CD47 expression on cell surface was significantly decreased after IR in both GSCs and non-GSCs, and less decrease on CD47 expression in GSCs comparing to matched non-GSCs were observed except for SHG141A (Fig. 1e)
Summary
Glioblastoma (GBM) is the most aggressive primary brain tumor with a high mortality rate. GBM patients typically respond initially to therapy, but tumor relapses within the high-dose irradiation field, suggesting the presence of a subpopulation of resistant cells. The small and rare cell subpopulation, termed glioma stem cells (GSCs), with stem-like properties including selfrenewal, multi-lineage differentiation potential and resistance to conventional treatments, has the ability to recapitulate the entire cell repertoire of the whole tumor[3,4]. RT is generally used as a primary therapy of localized tumors by inducing DNA damage and blocking the cell division. RT provokes the emission of immunogenic signals conveyed by damage-associated molecular patterns (DAMPs) molecules such as plasma membrane-exposed calreticulin (CRT), ATP and high mobility group box[1] (HMGB1) during the radiation-induced immunogenic cell death (ICD)[9]. DAMP molecules play a key role in the immunogenic potential to attract and activate dendritic cells (DCs) to phagocytose dying tumor cells, to process and present released tumor antigens to T cells[9,10]
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