The Tim-3-galectin-9 Secretory Pathway is Involved in the Immune Escape of Human Acute Myeloid Leukemia Cells
Isabel Gonçalves Silva,
Inna M. Yasinska,
Svetlana S. Sakhnevych,
Walter Fiedler,
Jasmin Wellbrock,
Marco Bardelli,
Luca Varani,
Rohanah Hussain,
Giuliano Siligardi,
Giacomo Ceccone,
Steffen M. Berger,
Yuri A. Ushkaryov,
Bernhard F. Gibbs,
Elizaveta Fasler-Kan,
Vadim V. Sumbayev
Affiliations
Isabel Gonçalves Silva
School of Pharmacy, University of Kent, Chatham Maritime, UK
Inna M. Yasinska
School of Pharmacy, University of Kent, Chatham Maritime, UK
Svetlana S. Sakhnevych
School of Pharmacy, University of Kent, Chatham Maritime, UK
Walter Fiedler
Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Germany
Jasmin Wellbrock
Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Germany
Marco Bardelli
Institute for Research in Biomedicine, Universita' della Svizzera italiana (USI), Bellinzona, Switzerland
Luca Varani
Institute for Research in Biomedicine, Universita' della Svizzera italiana (USI), Bellinzona, Switzerland
Rohanah Hussain
Beamline 23, Diamond Light Source, Didcot, UK
Giuliano Siligardi
Beamline 23, Diamond Light Source, Didcot, UK
Giacomo Ceccone
European Commission Joint Research Centre, Ispra, Italy
Steffen M. Berger
Department of Pediatric Surgery and Department of Clinical Research, Children's Hospital, Inselspital, University of Bern, Switzerland
Yuri A. Ushkaryov
School of Pharmacy, University of Kent, Chatham Maritime, UK
Bernhard F. Gibbs
School of Pharmacy, University of Kent, Chatham Maritime, UK
Elizaveta Fasler-Kan
Department of Pediatric Surgery and Department of Clinical Research, Children's Hospital, Inselspital, University of Bern, Switzerland
Vadim V. Sumbayev
School of Pharmacy, University of Kent, Chatham Maritime, UK
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.
