The Tim-3-Galectin-9 Pathway and Its Regulatory Mechanisms in Human Breast Cancer

Abstract

Human cancer cells operate a variety of effective molecular and signaling mechanisms which allow them to escape host immune surveillance and thus progress the disease. We have recently reported that the immune receptor Tim-3 and its natural ligand galectin-9 are involved in the immune escape of human acute myeloid leukemia (AML) cells. These cells use the neuronal receptor latrophilin 1 (LPHN1) and its ligand fibronectin leucine rich transmembrane protein 3 (FLRT3, and possibly other ligands) to trigger the pathway. We hypothesized that the Tim-3-galectin-9 pathway may be involved in the immune escape of cancer cells of different origins. We found that studied breast tumors expressed significantly higher levels of both galectin-9 and Tim-3 compared to healthy breast tissues of the same patients and that these proteins were co-localized. Increased levels of LPHN2 and expressions of LPHN3 as well as FLRT3 were also detected in breast tumor cells. Activation of this pathway facilitated the translocation of galectin-9 onto the tumor cell surface, however no secretion of galectin-9 by tumor cells was observed. Surface-based galectin-9 was able to protect breast carcinoma cells against cytotoxic T cell-induced death. Furthermore, we found that cell lines from brain, colorectal, kidney, blood/mast cell, liver, prostate, lung, and skin cancers expressed detectable amounts of both Tim-3 and galectin-9 proteins. The majority of cell lines expressed one of the LPHN isoforms and FLRT3. We conclude that the Tim-3-galectin-9 pathway is operated by a wide range of human cancer cells and is possibly involved in prevention of anti-tumor immunity.

Transforming growth factor beta type 1 (TGF-β) and hypoxia-inducible factor 1 (HIF-1) transcription complex as master regulators of the immunosuppressive protein galectin-9 expression in human cancer and embryonic cells

“…This was in line with the highly increased amounts of tumourassociated TGF-β and intracellular levels of phospho-S423/S425-Smad3 (active form, Figure 1C). In line with our previous observations [1], levels of both Tim-3 and galectin-9 were substantially increased in AGING tumour tissues compared to non-malignant samples ( Figure 1D).…”

“…Galectin-9 plays a crucial role in determining the ability of cancer cells to escape host immune surveillance [1,2]. As with all galectins, galectin-9 lacks a secretion signal sequence and thus requires trafficking in order to be externalised onto the cell surface or secreted [1,7]. Cell surface-based or secreted galectin-9 can impair anti-cancer activities of NK and cytotoxic T cells [1,2,6,7].…”

“…Galectin-9 is one of the crucial proteins used by various types of cancer cells to suppress cytotoxic immune responses and thus, escape immune surveillance [1]. Some cancer cells (acute myeloid leukaemia (AML) and colorectal cancer) are capable of secreting this protein, while other cancer cells translocate galectin-9 onto the surface [1] and use it to impair anti-cancer activities of cytotoxic lymphoid cells such as cytotoxic T lymphocytes and natural killer (NK) cells [1][2][3][4][5][6]. Galectin-9 lacks a secretion signal sequence and thus cannot be secreted on its own.…”

“…Human cancer cells express significantly higher levels of galectin-9 compared to healthy human cells [1]. In particular, high amounts of galectin-9 are secreted by AML and colorectal cancer cells [1,14]. However, the biochemical mechanisms underlying increased galectin-9 expression in human cancer cells are unknown.…”

Galectins as Checkpoints of the Immune System in Cancers, Their Clinical Relevance, and Implication in Clinical Trials

“…With more than 150 publications per year in the last three years, the Gal-9/TIM-3 interaction is one of the most studied to be responsible for the immune tolerance in cancer. The Gal-9/TIM-3 pathway is functional in a wide range of human cancer cells [66]. Thus, it is important to ascertain whether Gal-9 has therapeutic potential in human diseases, including cancer, by influencing T cell immunity and inducing apoptosis of specific T-cell subpopulations like other galectins do.…”