Tim-3-galectin-9 immunosuppressive pathway in human acute myeloid leukaemia and solid tumour cells and biochemical functions of its crucial components

Cancer is one of the primary causes of human death worldwide. Acute myeloid leukaemia (AML), one of the most severe types of blood/bone marrow cancers, is derived from transformed human myeloid precursor cells which developed mechanisms allowing them to escape host immune surveillance by inactivating cytotoxic lymphoid cells. Further studies suggested that solid tumours operate similar immune escape strategies. Molecular mechanisms of the immune evasion by malignant cells are poorly understood, however a better comprehension of the biochemistry underlying these processes are vital for development of anti-cancer immunotherapy - a cure of new generation. Recent evidence suggested the crucial involvement of Tim-3 and galectin-9 proteins in the immunosuppression operated by malignant cells. Therefore, the aim of our work was to investigate the activity of Tim-3-galectin-9 immunosuppressive pathway in human malignant cells and biochemical functions of its crucial components. We discovered that triggering of the receptor called latrophilin (LPHN) 1, expressed in AML cells but absent in healthy leukocytes, induces biosynthesis and exocytosis of T-cell immunoglobulin and mucin domain 3 (Tim-3) and galectin-9. Galectin-9 suppresses anti-cancer immunity by impairing anti-cancer activities of cytotoxic lymphoid cells. Tim-3 is trafficking galectin-9 but also can act on its own and prevent generation of interleukin-2 (IL-2) required for activation of cytotoxic lymphoid cells. Furthermore, AML cells recruit crucial components of normal human metabolism to escape surveillance and progress the disease. In particular, human adrenal cortex hormone cortisol upregulates LPHN1 expression in AML cells; blood-available fibronectin leucine rich transmembrane protein 3 (FLRT3) interacts with LPHN1 leading to galetin-9/Tim-3 synthesis and exocytosis in AML cells. Crucial components of FLRT3/LPHN/Tim-3/galectin-9 pathway are expressed in the majority of cancer cell lines and thus may be common for a variety of malignant tumours. Tim-3-galectin-9 pathway is active in breast cancer and variety of other solid tumour cells and is used to protect malignant cells from host immune attack. However, unlike some other members of galectin family of proteins (for example, galectin-3), galectin-9 doesn't protect cancer cells against apoptosis via mitochondrial defunctionalisation. On the other hand, mitochondrial defunctionalisation reduces galectin-9 surface expression and leads to its accumulation in mitochondria in malignant cells but not in healthy ones. Therefore, targeted mitochondrial defunctionalisation may be a novel strategy for anti-cancer immunotherapy, since it would reduce galectin-9 surface expression allowing better elimination of cancer cells by immune system cells. Taken together our work demonstrates for the first time that Tim-3-galectin-9 immunosuppressive pathway plays a pivotal role in protection of AML and various solid tumour cells towards host immune surveillance - the machinery operated by cytotoxic lymphoid cells.