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

DOI: 10.1016/j.ebiom.2017.07.018 DOI Help

Authors: Isabel Gonçalves Silva (University of Kent) , Inna M. Yasinska (University of Kent) , Svetlana S. Sakhnevych (University of Kent) , Walter Fiedler (University Medical Center Hamburg-Eppendorf) , Jasmin Wellbrock (University Medical Center Hamburg-Eppendorf) , Marco Bardelli (Universita' della Svizzera italiana (USI)) , Luca Varani (Universita' della Svizzera italiana (USI)) , Rohanah Hussain (Diamond Light Source) , Giuliano Siligardi (Diamond Light Source) , Giacomo Ceccone (European Commission Joint Research Centre) , Steffen M. Berger (University of Bern) , Yuri A. Ushkaryov (University of Kent) , Bernhard F. Gibbs (University of Kent; University of Oldenburg) , Elizaveta Fasler-kan (University of Bern; University of Basel) , Vadim V. Sumbayev (University of Kent)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Ebiomedicine

State: Published (Approved)
Published: July 2017
Diamond Proposal Number(s): 12578

Open Access Open Access

Abstract: 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.

Journal Keywords: Acute myeloid leukemia; Tim-3; Galectin-9; NK cells; Anti-leukemia immunity

Subject Areas: Biology and Bio-materials, Medicine


Instruments: B23-Circular Dichroism

Added On: 26/07/2017 09:19

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