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

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.