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  2. 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

  • FASEB J. 2020 Jun;34(6):8442-8458. doi: 10.1096/fj.201902186R.
Tao Shen 1 Zihang Huang 1 Chengfei Shi 2 Xiaofan Pu 1 Xiaodong Xu 1 Zhengrong Wu 1 Guoping Ding 1 Liping Cao 1 3
Affiliations

Affiliations

  • 1 Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • 2 Department of General Surgery, Wenling Hospital, School of Medicine, Wenzhou Medical University, Wenling, China.
  • 3 Innovation Center for Minimally Invasive Technique and Device, Zhejiang University, Hangzhou, China.
Abstract

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.

Keywords

T lymphocytes; apoptosis; endoplasmic reticulum stress; exosomes; p38 MAPK; pancreatic cancer.

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