TIM-3 and Galectin-9 Pathway

Introduction

TIM-3 (CD366; also known as HAVCR2) is one of the immune checkpoint molecules with potential cancer immunology relevance. Its levels are particularly elevated on dysfunctional and exhausted T cells suggesting an essential role in malignancy. Modulation of this pathway occurs through four relevant ligands-namely, galectin-9 (Gal-9), phosphatidylserine (PtdSer), high mobility group protein B1 (HMGB1), and carcinoembryonic antigen cell adhesion molecule 1 (Ceacam-1). It is noteworthy that galectin-9 is the first identified natural ligand and specifically recognizes N-linked sugar chains' structure in the TIM-3 IgV domain. Galectin-9 is produced broadly by immune cells, including mast cells, T cells, B cells, macrophages, and also by non-immune cells, including the epithelium of the gastrointestinal tract, endothelial cells, and fibroblasts.

The binding of galectin-9 by the TIM-3 receptor triggers downstream signaling to regulate T cell survival and function negatively. Galectin-9 binding results in the oligomerization of TIM-3 on the cell surface and then causes the release of Bat3 from the cytoplasmic tail of TIM-3. This, in turn, leads to the inhibition of T helper 1 (TH1) cell responses and may be one of the mechanisms by which T cells enter the state of dysfunction or exhaustion. The secretion of both TIM-3 and galectin-9 allows cancer cells to evade immune surveillance. Collectively, activation of the TIM-3/galectin-9 pathway suppresses immune responses and facilitates tumor growth by promoting Treg cells to inhibit the cytotoxic function of Th1 and CD8⁺ T cells.

Preclinical and Clinical Development of Drugs for TIM-3 and Galectin-9 Pathway

TIM-3/galectin-9 mediates immune tolerance and has possible implications in the suppression of host anti-cancer immune surveillance. This pathway can be recommended for the design of novel anti-cancer immunotherapeutic approaches based on inhibiting the TIM-3/galectin-9 pathway, thus enabling the immune system to attack and eradicate malignant tumors. To date, several immunotherapeutic agents targeting TIM-3 are currently in clinical trials as monotherapy or in combination with other receptor blockade strategies. All the preclinical and clinical data show that the design of novel agents that broadly block multiple TIM-3-ligand pathways may further improve the efficacy of existing combinatorial immunotherapies and, thus, increase the survival of patients.

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