State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection and Collaborative InnovationCenter of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, Jiangsu, China.
Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 215006, Suzhou, Jiangsu, China.
Cell Death Dis. 2020 Sep 22;11(9):786. doi: 10.1038/s41419-020-03000-z.
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.
肿瘤在照射野外部位的消退被认为与损伤相关分子模式（DAMPs）分子的释放和免疫原性细胞死亡（ICD）的产生有关。神经胶质瘤干细胞（GSCs）对高剂量辐射具有抗性，并且最终选择生长出更具侵袭性的肿瘤。这项研究表明，与匹配的非 GSCs 相比，高剂量 IR 触发的 DAMPs 分子暴露和释放更少。结合免疫球蛋白蛋白（Bip）的下调促进了 PERK 和 IRE1-α磷酸化介导的内质网应激，以产生 DAMPs 分子，并增加树突状细胞成熟和效应 T 淋巴细胞的激活。用 Bip 敲低和 IR 处理的 GSCs 有效地防止了肿瘤的发生，并减少了放疗后的肿瘤复发。这些数据表明，Bip 在抑制 GSCs 中 IR 诱导的 ICD 中起着关键作用，Bip 抑制可能通过改善肿瘤免疫微环境成为辅助治疗的有前途的策略。
