TIM-3: An Emerging Immuno-Oncology Target

TIM-3 is an Inhibitory Receptor that Binds Gal-9, CEACAM-1, and HMGB1 

T cell immunoglobulin- and mucin-domain-containing 3 (TIM-3), also known as Hepatitis A virus cellular receptor 2 (HAVCR2), is a member of the TIM family of proteins, which consists of TIM-1, TIM-3, and TIM-4 in humans and TIM-1-8 in mice.¹ TIM family proteins are type I transmembrane glycoproteins with an extracellular domain consisting of an N terminal IgV-like domain, a mucin-like domain and a stalk domain, with potential O- and N-linked glycosylation sites, respectively. The extracellular domain is followed by a transmembrane segment, and with the exception of TIM-4, a cytoplasmic tail with a conserved region of five tyrosine residues that are critical for downstream signaling.^2,3 TIM-3 is expressed on IFN-gamma-producing CD8⁺ T cells and Th1 cells, and at lower levels on Th17 cells, and has been shown to negatively regulate T cell proliferation and cytokine production.^1-6 Additionally, TIM-3 is expressed on subsets of regulatory T cells, dendritic cells (DCs), macrophages, monocytes, and mast cells.^{7, 8} Similar to PD-1, it is also highly expressed on exhausted T cells and natural killer cells in chronic infections and in cancer.^9-12

The IgV domain of the TIM-3 protein has been shown to bind to four different ligands, including galectin-9, phosphatidylserine (PtdSer), high mobility group protein B1 (HMGB1), and CEACAM-1.^13-18 Galectin-9, the first identified TIM-3 ligand, was found to bind to the carbohydrate motif in the IgV domain of TIM-3 and induce Th1 cell apoptosis.¹³ In contrast to Galectin-9, which has a distinct binding site on the TIM-3 protein, the other TIM-3 ligands have overlapping binding sites in the FG-CC’ loop region in the IgV domain of the TIM-3 protein.³ PtdSer is a molecule that is exposed on the surface of apoptotic cells that binds not only to TIM-3, but also to TIM-1 and TIM-4, and has been implicated in macrophage and dendritic cell-mediated uptake of apoptotic cells and antigen cross-presentation.¹⁹ HMGB1 is a damage-associated molecule that has also been shown to bind to the TIM-3 protein.¹⁶ HMGB1 is released by stressed or dying cells and plays a role in transporting nucleic acids into endosomes, which is necessary to promote activation of the innate immune response against pathogens and tumors. Binding of HMGB1 to TIM-3 interferes with this process and therefore inhibits innate immunity and the anti-tumor immune response. Finally, the TIM-3 protein interacts with CEACAM-1 and the cis interaction between these two proteins has been shown to be required for TIM-3 glycosylation, stability, and its ability to inhibit T cell functions.^3,17 The CEACAM-1 and TIM-3 proteins can also interact in trans to negatively regulate T cell responses.³

TIM-3 is highly expressed on CD8⁺ tumor-infiltrating lymphocytes (TILs) and on CD4⁺ regulatory T cells in multiple forms of cancer.^{3, 7, 11, 20, 21} All TIM-3⁺ CD8⁺ TILs co-express PD-1 and these T cells represent the most dysfunctional population of CD8⁺ TILs in both mouse tumor models and in many different types of human cancer.²² While blockade of TIM-3 alone was shown to have variable effects in different mouse tumor models, blockade of both TIM-3 and PD-1 was found to synergistically reduce tumor growth.^{9, 22-24} The positive anti-tumor effects observed by combined TIM-3/PD-1 blockade was attributed to both restoring the function of exhausted CD8⁺ TILs, including tumor antigen-specific T cell proliferation and cytokine production, as well as inhibiting the immunosuppressive functions of TIM-3⁺ regulatory T cells. Additionally, combined TIM-3/PD-1 blockade may improve anti-tumor immune responses by restoring the activity of exhausted natural killer cells, inhibiting the Galectin-9-TIM-3-mediated expansion of immunosuppressive myeloid-derived suppressor cells (MDSCs), and/or preventing TIM-3 on intratumoral DCs from interacting with HMGB1, thereby restoring activation of the innate immune response by tumor cell-derived nucleic acids. ^25,26 Therefore, combination therapies targeting TIM-3 and PD-1 or CTLA-4, or those which target TIM-3 in combination with agonist antibodies for T cell co-stimulatory receptors warrant further exploration.

Bio-Techne's R&D Systems^TM brand offers bioactive recombinant proteins for TIM-3, Galectin-9, CEACAM-1, and HMGB1, along with fluorochrome-conjugated antibodies for detecting these molecules to further our understanding of the immunosuppressive functions of TIM-3 and its ligands.

TIM-3 and TIM-3 Ligands - Products by Molecule

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