Tim-3 as a signalling receptor expressed by leukaemia cells and potential target for highly specific drug delivery

• Main Author: Bernardo Goncalves Oliveira Silva, Isabel
• Format: Dissertation
• Language: English
• Published: University of Kent 2017

Leukaemia is a blood/bone marrow cancer caused by malignant immature hematopoietic precursors, and quickly becomes a systematic malignancy. The most severe type of leukaemia that has the highest number of lethal outcomes is Acute Myeloid Leukaemia (AML) where malignant cells escape host immune surveillance by inactivating cytotoxic lymphoid cells. We discovered a fundamental biochemical mechanism in AML cells, which includes ligand dependent (probably FLRT3) activation of ectopically expressed latrophilin 1 and possible other G-protein coupled receptors, leading to upregulated translation and secretion of the immune receptor Tim-3 and its ligand galectin-9. This process involved protein kinase C and the mammalian target of rapamycin (mTOR). Tim-3 was observed to participate in galectin-9 secretion, and was also released in a free soluble form. Galectin-9 impaired the anti-cancer activities of cytotoxic lymphoid cells including natural killer (NK) cells and soluble Tim-3 prevented the secretion of interleukin-2 (IL-2), which was required for the activation of cytotoxic lymphoid cells. These results were validated in ex vivo experiments, using primary samples from AML patients. This fundamental pathway provides reliable targets for both highly specific diagnosis and immune therapy of AML. Furthermore, we demonstrated that the Tim-3/galectin-9 autocrine loop has intracellular functions and promotes cell growth and proliferation by directly upregulating translational pathway controlled by mTOR.