期刊
EBIOMEDICINE
卷 22, 期 -, 页码 44-57出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ebiom.2017.07.018
关键词
Acute myeloid leukemia; Tim-3; Galectin-9; NK cells; Anti-leukemia immunity
资金
- Daphne Jackson Trust postdoctoral fellowship
- University of Kent Faculty of Sciences Research Fund
- Batzebar grant
- Oncosuisse grant [KFS-3728-08-2015]
Acute myeloid leukemia (AML) is a severe and often fatal systemic malignancy. Malignant cells are capable of escaping host immune surveillance by inactivating cytotoxic lymphoid cells. In this work we discovered a fundamental molecular pathway, which includes ligand-dependent activation of ectopically expressed latrophilin 1 and possibly other G-protein coupled receptors leading to increased translation and exocytosis of the immune receptor Tim-3 and its ligand galectin-9. This occurs in a protein kinase C and mTOR (mammalian target of rapamycin)-dependent manner. Tim-3 participates in galectin-9 secretion and is also released in a free soluble form. Galectin-9 impairs the anti-cancer activity of cytotoxic lymphoid cells including natural killer (NK) cells. Soluble Tim-3 prevents secretion of interleukin-2 (IL-2) required for the activation of cytotoxic lymphoid cells. These results were validated in ex vivo experiments using primary samples from AML patients. This pathway provides reliable targets for both highly specific diagnosis and immune therapy of AML. (C) 2017 Published by Elsevier B.V.
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