Adenosine leakage from perforin-burst extracellular vesicles inhibits perforin secretion by cytotoxic T-lymphocytes

Autor: Tomoyoshi Soga, Yusuke Yoshioka, Ryuhei Kudo, Masako Hasebe, Juntaro Matsuzaki, Akiyoshi Hirayama, Takahiro Ochiya, Hiroko Tadokoro, Yusuke Yamamoto, Masahiro Sugimoto
Rok vydání: 2019
Předmět:
0301 basic medicine
Metabolic Analysis
Adenosine
Physiology
Glycobiology
Biochemistry
0302 clinical medicine
Adenosine deaminase
Metabolites
Medicine and Health Sciences
Cytotoxic T cell
Cells
Cultured
Protein Metabolism
Multidisciplinary
biology
Chemistry
Drugs
hemic and immune systems
Nucleosides
Immunosuppressives
Glycosylamines
Cell biology
Bioassays and Physiological Analysis
030220 oncology & carcinogenesis
Medicine
medicine.drug
Research Article
Cell Physiology
Science
chemical and pharmacologic phenomena
Research and Analysis Methods
03 medical and health sciences
Extracellular Vesicles
Interferon-gamma
Cell Line
Tumor
medicine
Extracellular
Humans
Metabolomics
Secretion
Pharmacology
Tumor microenvironment
Perforin
Biology and Life Sciences
Cell Biology
Adenosine receptor
Cell Metabolism
030104 developmental biology
Metabolism
biology.protein
Physiological Processes
T-Lymphocytes
Cytotoxic
Zdroj: PLoS ONE
PLoS ONE, Vol 15, Iss 4, p e0231430 (2020)
ISSN: 1932-6203
Popis: Extracellular vesicles (EVs) in the tumor microenvironment facilitate intercellular communication. Cancer cell-derived EVs act as an immunosuppressor by transporting cargos and presenting transmembrane proteins. By contrast, CD8+ cytotoxic T-lymphocytes (CTLs) exert anti-cancer cytotoxicity via the pore-forming protein perforin. Here, we hypothesize that although EVs are destroyed by perforin, cancer cell-derived EVs might possess mechanisms that enable them to avoid this destruction. We used a breast cancer cell line, MDA-MB-231-luc-D3H2LN (D3H2LN), to generate EVs. Destruction of the EVs by perforin was demonstrated visually using atomic force microscopy. To investigate immunosuppressive metabolites within cancer cell-derived EVs, we performed metabolomic profiling of EVs from D3H2LN cells cultured for 48 h with or without IFN-γ, which induces metabolic changes in the cells. We found that both types of EV from IFN-γ treated D3H2LN cells and non-treated D3H2LN cells contained adenosine, which has immunosuppressive effects. When we exposed cancer cell-derived EVs to CTLs, perforin secretion by CTLs fell significantly. In addition, the decreases in perforin secretion were ameliorated by treatment with adenosine deaminase, which degrades extracellular adenosine. Taken together, these results suggest that after perforin secreted by CTLs disrupts the membrane of EVs, adenosine released from the EVs acts as an immunosuppressive metabolite by binding to the adenosine receptor on the CTL membrane. This mechanism provides a novel survival strategy using cancer cell-derived EVs.
Databáze: OpenAIRE
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