Targeting endoplasmic reticulum associated degradation pathway combined with radiotherapy enhances the immunogenicity of esophageal cancer cells

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.

Comments：

The study aimed to investigate the effectiveness of inhibiting endoplasmic reticulum-associated protein degradation (ERAD) pathways in enhancing radiation-induced immunogenic cell death (ICD) in esophageal cancer (EC). The study found that inhibiting ERAD pathways could stimulate ICD component emission from dying EC cells in a dose-dependent pattern. When combined with moderate dose radiation therapy (RT), ERAD inhibitors were able to stimulate increased ICD in EC cells. This dual therapy could elicit an antitumor immune response by enhancing dendritic cells' maturation and phagocytosis.

The study also revealed a significant correlation between ICD hallmark genes, especially calreticulin (CALR), and tumor-infiltrating immune cells. Low expression of adenosine triphosphate (ATP) and high mobility group protein B1 (HMGB1) and high expression of CALR were associated with favorable survival in patients with EC. The findings suggest that ERAD inhibitors combined with moderate doses of RT can enhance the immunogenicity of EC cells, leading to an enhanced antitumor immune response.

Overall, the study highlights an important method to improve the immunogenicity of EC cells, which could lead to better clinical outcomes.