Laboratory of Radiation Oncology, the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China.
Academic of Medical Science, Zhengzhou University, Zhengzhou, China.
Cancer Biol Ther. 2023 Dec 31;24(1):2166763. doi: 10.1080/15384047.2023.2166763.
Immunogenic cell death (ICD) is essential for the activation of immune system against cancer. We aimed to investigate the efficacy of endoplasmic reticulum (ER)-associated protein degradation (ERAD) inhibitors (EerI and NMS-873) in enhancing radiation-induced ICD in esophageal cancer (EC). EC cells were administered with ERAD inhibitors, radiation therapy (RT), and the combination treatment. ICD hallmarks including calreticulin (CALR), adenosine triphosphate (ATP), and high mobility group protein B1 (HMGB1) were detected. The efficacy of ERAD inhibitors combined with RT in stimulating ICD was analyzed. Additionally, the role of ICD hallmarks in immune cell infiltration and patient survival was investigated. Inhibiting ERAD pathways was able to stimulate ICD component emission from dying EC cells in a dose-dependent pattern. Radiation-induced ICD was significantly increased after high doses RT (≥10 Gy). ERAD inhibitor combined with moderate dose RT (≥6 Gy) was capable of stimulating increased ICD in EC cells. Dual therapy could elicit the antitumor immune response by enhancing dendritic cells maturation and phagocytosis. Further investigation revealed a significant correlation between CALR and tumor-infiltrating immune cells. Low expression of ATP and HMGB1 and high expression of CALR were associated with favorable survival in patients with EC. The immunogenicityof EC can be enhanced by ERAD inhibitors combined with moderate doses of RT. ICD hallmark genes, especially CALR, are correlated to immune cell infiltration and clinical outcomes in EC. The present results demonstrated an important method to improve the immunogenicity of EC cells for enhanced antitumor immune response.
免疫原性细胞死亡（ICD）对于激活机体免疫系统对抗癌症至关重要。本研究旨在探讨内质网（ER）相关蛋白降解（ERAD）抑制剂（EerI 和 NMS-873）增强食管癌（EC）放射诱导 ICD 的疗效。给予 EC 细胞 ERAD 抑制剂、放射治疗（RT）及联合治疗。检测 ICD 特征标志物包括钙网织蛋白（CALR）、三磷酸腺苷（ATP）和高迁移率族蛋白 B1（HMGB1）。分析 ERAD 抑制剂联合 RT 刺激 ICD 的效果。此外，还研究了 ICD 标志物在免疫细胞浸润和患者生存中的作用。抑制 ERAD 通路可促进死亡 EC 细胞 ICD 成分以剂量依赖性方式释放。高剂量 RT（≥10Gy）后可显著增加放射诱导的 ICD。ERAD 抑制剂联合中剂量 RT（≥6Gy）可刺激 EC 细胞 ICD 增加。双重治疗可通过增强树突状细胞成熟和吞噬作用引发抗肿瘤免疫反应。进一步研究表明，CALR 与肿瘤浸润免疫细胞之间存在显著相关性。ATP 和 HMGB1 低表达、CALR 高表达与 EC 患者的良好生存相关。ERAD 抑制剂联合中剂量 RT 可增强 EC 的免疫原性。ICD 特征基因，尤其是 CALR，与 EC 中的免疫细胞浸润和临床结局相关。本研究结果为提高 EC 细胞的免疫原性以增强抗肿瘤免疫反应提供了一种重要方法。
