The Tim-3-galectin-9 Secretory Pathway is Involved in the Immune Escape of Human Acute Myeloid Leukemia Cells

Acutemyeloid leukemia (AML) is a severe and often fatal systemicmalignancy. 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.

GONÇALVES SILVA Isabel;  YASINSKA Inna M.;  SAKHNEVYCH Svetlana S.;  FIEDLER Walter;  WELLBROCK Jasmin;  BARDELLI Marco;  VARANI Luca;  HUSSAIN Rohanah;  SILIGARDI Giuliano;  CECCONE Giacomo;  BERGER Steffen M.;  USHKARYOV Yuri A.;  GIBBS Bernhard F.;  FASLER-KAN Elizaveta;  SUMBAYEV Vadim; 

2017-12-14

ELSEVIER SCIENCE BV

JRC107578

2352-3964,   

https://publications.jrc.ec.europa.eu/repository/handle/JRC107578,   

10.1016/j.ebiom.2017.07.018,