Pancreatic cancer-derived exosomes induce apoptosis of T lymphocytes through the p38 MAPK-mediated endoplasmic reticulum stress
Pancreatic cancer-derived exosomes induce apoptosis of T lymphocytes through the p38 MAPK-mediated endoplasmic reticulum stress
复制标题
胰腺癌来源的外泌体通过p38 MAPK介导的内质网应激诱导T淋巴细胞凋亡
DOI：
10.1096/fj.201902186r
复制
发表时间：
2020-04-29
期刊：
影响因子：
4.8
通讯作者：
Cao, Liping
中科院分区：
文献类型：
--
作者：
Shen, Tao;Huang, Zihang;Cao, Liping
胰腺癌是第四大致死性恶性肿瘤，其特征在于免疫原性差。胰腺癌细胞具有多种策略来抑制宿主免疫应答，逃避免疫防御，并促进肿瘤生长和发育。作为长距离细胞间通讯的一种模式，癌症来源的外泌体有助于免疫系统的损害。然而，诱导受肿瘤来源的外泌体影响的免疫细胞中信号转导途径活性变化的机制知之甚少。我们（1）用胰腺癌来源的外泌体处理外周T淋巴细胞，用tdTomato标记CD 63，以追踪外泌体从胰腺癌细胞转移到T淋巴细胞;（2）使用真实的时间细胞分析系统进行外泌体处理的T淋巴细胞的细胞毒性测定;（3）通过RNA测序和基因组富集分析，探索外泌体处理的T淋巴细胞中介导凋亡的关键信号通路;（4）证实了p38丝裂原活化蛋白激酶（MAPK）和内质网（ER）应激在exosome诱导的T淋巴细胞凋亡中的作用。总之，这些结果表明胰腺癌细胞分泌外泌体，其被T淋巴细胞摄取以激活p38 MAPK，然后诱导ER应激介导的凋亡，最终引起免疫抑制。
Pancreatic cancer is the fourth most lethal malignancy and is characterized by poor immunogenicity. Pancreatic cancer cells have various strategies to suppress host immune response, evade immune defenses, and facilitate tumor growth and development. As a mode of long-range intercellular communication, cancer-derived exosomes contribute to impairment of the immune system. However, the mechanisms that induce changes in the activities of signal transduction pathways in immune cells, which are influenced by tumor-derived exosomes, are poorly understood. We (1) treated peripheral T lymphocytes with pancreatic cancer-derived exosomes, tagged CD63 with tdTomato, to trace exosome transfer from pancreatic cancer cells to T lymphocytes; (2) carried out a cytotoxicity assay of exosome-treated T lymphocytes using the Real Time Cellular Analysis system; (3) performed RNA sequencing and gene set enrichment analysis to explore the pivotal signaling pathway that mediates apoptosis in exosome-treated T lymphocytes; and (4) demonstrated the role of p38 mitogen-activated protein kinase (MAPK) and endoplasmic reticulum (ER) stress in exosome-induced T-lymphocyte apoptosis. In conclusion, these results indicate that pancreatic cancer cells secrete exosomes, which are taken up by T lymphocytes to activate p38 MAPK, and then induce ER stress-mediated apoptosis, ultimately causing immunosuppression.