Bip inhibition in glioma stem cells promotes radiation-induced immunogenic cell death

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.

Immunogenic cell death and its therapeutic or prognostic potential in high-grade glioma

“…However, certain cancer cell autonomous mechanisms regulating proteostasis can either subvert danger signaling pathways (like the PERK-eiF2α axis [ 66 ]), cause retention of DAMPs thereby impairing the proficient dialogue between dying cancer cells and the immune system or secrete mutate forms of DAMPs (like mutant CRT) which supposed to act as a decoy for DCs in the wild-type [ 67 ]. For example, in glioma Bip upregulation, a typical marker of the activation of the unfolded protein response, restricted DAMPs exposure and release in glioma stem cells [ 68 ]. A recent study also reported that cancer cells may avoid the exposure of CRT through a mechanism involving stanniocalcin-1 mediated retention of CRT in the cytoplasm (thus suggesting a pool of cytosolic CRT), a process that impairs phagocytosis by antigen-presenting cells and subsequent anticancer adaptive immunity [ 67 ].…”

Immunogenic Cell Death Induction by Ionizing Radiation

“…It has also been reported that Bip expression is associated with increased tumor progression ( 96 ). Accordingly, Bip inhibition can inhibit tumor growth by enhancing ER stress to elicit cDAMPs release or exposure to activate antitumor immunity ( 78 ). The combination of Bip inhibition and 10 Gy IR enhanced IR-induced ICD with increased CRT exposure, ATP secretion, and HMGB1 release and promoted the phagocytosis and maturation of DCs.…”

“…The combination of Bip inhibition and 10 Gy IR enhanced IR-induced ICD with increased CRT exposure, ATP secretion, and HMGB1 release and promoted the phagocytosis and maturation of DCs. As a vaccine, glioma stem cells treated with Bip inhibition and IR could delay tumor generation efficiently, facilitate the proliferation of CD4 + and CD8 + T cells, and decrease Treg cell infiltration in vivo ( 78 ).…”

Unconventional Protein Secretion in Brain Tumors Biology: Enlightening the Mechanisms for Tumor Survival and Progression

“…Indeed, gliomas do present high levels of glycolysis, also due to the hypoxia, which supports tumor growth, and this mechanism may be regulated by PERK and the activation of Akt signaling ( Hou et al, 2015 ). The inhibition of upstream effectors of PERK sensitizes GSCs to radiotherapy and decreases recurrence ( Yang et al, 2020 ). Furthermore, PERK modulates angiogenesis in GBM in hypoxic conditions ( Soni et al, 2020 ), and it is correlated with the stem-like cell phenotype through the modulation of SOX2 expression ( Penaranda-Fajardo et al, 2019 ).…”