Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
Biochem Biophys Res Commun. 2024 Nov 12;733:150665. doi: 10.1016/j.bbrc.2024.150665. Epub 2024 Sep 5.
Immunogenic cell death (ICD) enhances immunogenicity and activates antitumor immune responses. ICD induction by anticancer drugs may be effective against microsatellite-stable colorectal cancers (CRCs) that are less responsive to immune checkpoint inhibitors. Calreticulin (CRT) is crucial in ICD, promoting dendritic cell phagocytosis and initiating antitumor immunity. This study investigated CRT exposure mechanisms in four CRC cell lines and three human CRC organoids. Flow cytometry and immunofluorescence showed that oxaliplatin and 5-fluorouracil caused CRT exposure in all models. Despite CRT's association with endoplasmic reticulum stress, Western blot analysis showed no increase in this stress. These findings suggest alternative pathways. RNA sequencing identified enrichment of p53 signaling pathway genes, including TP53I3, TP53INP1, and YPEL3, which were confirmed by RT-qPCR. These results suggest that the p53 signaling pathway plays an important role in CRT exposure induced by anticancer drugs.
免疫原性细胞死亡 (ICD) 增强了免疫原性并激活了抗肿瘤免疫反应。抗癌药物诱导的 ICD 可能对免疫检查点抑制剂反应性较低的微卫星稳定结直肠癌 (CRC) 有效。钙网蛋白 (CRT) 在 ICD 中至关重要，可促进树突状细胞吞噬并引发抗肿瘤免疫。本研究调查了四个 CRC 细胞系和三个人类 CRC 类器官中的 CRT 暴露机制。流式细胞术和免疫荧光显示奥沙利铂和 5-氟尿嘧啶在所有模型中均导致 CRT 暴露。尽管 CRT 与内质网应激有关，但 Western blot 分析显示该应激没有增加。这些发现表明存在替代途径。RNA 测序鉴定了 p53 信号通路基因的富集，包括 TP53I3、TP53INP1 和 YPEL3，这些基因通过 RT-qPCR 得到了证实。这些结果表明，p53 信号通路在抗癌药物诱导的 CRT 暴露中发挥重要作用。
