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Pancreatic cancer‐derived exosomes induce apoptosis of T lymphocytes through the p38 MAPK‐mediated endoplasmic reticulum stress
Author(s) -
Shen Tao,
Huang Zihang,
Shi Chengfei,
Pu Xiaofan,
Xu Xiaodong,
Wu Zhengrong,
Ding Guoping,
Cao Liping
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201902186r
Subject(s) - microvesicles , exosome , pancreatic cancer , immune system , cancer research , microbiology and biotechnology , endoplasmic reticulum , biology , signal transduction , unfolded protein response , apoptosis , immunology , cancer , microrna , genetics , biochemistry , gene
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.