TIGIT

Official Full Name

T cell immunoreceptor with Ig and ITIM domains

Organism

Homo sapiens

GeneID

201633

Background

This gene encodes a member of the PVR (poliovirus receptor) family of immunoglobin proteins. The product of this gene is expressed on several classes of T cells including follicular B helper T cells (TFH). The protein has been shown to bind PVR with high affinity; this binding is thought to assist interactions between TFH and dendritic cells to regulate T cell dependent B cell responses.[provided by RefSeq, Sep 2009]

Synonyms

VSIG9; VSTM3; WUCAM;

Protein Sequence

MRWCLLLIWAQGLRQAPLASGMMTGTIETTGNISAEKGGSIILQCHLSSTTAQVTQVNWEQQDQLLAICNADLGWHISPSFKDRVAPGPGLGLTLQSLTVNDTGEYFCIYHTYPDGTYTGRIFLEVLESSVAEHGARFQIPLLGAMAATLVVICTAVIVVVALTRKKKALRIHSVEGDLRRKSAGQEEWSPSAPSPPGSCVQAEAAPAGLCGEQRGEDCAELHDYFNVLSYRSLGNCSFFTETG

Open

Disease

Cervical cancer, Lung cancer, Non-small-cell lung cancer, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

8 +

Discontinued Drug

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Cat.No.	Product Name	Tag	Price

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Detailed Information

TIGIT was first identified as an immune checkpoint in 2009 to inhibit the activation of T cells and NK cells. The TIGIT receptor has a transmembrane domain, an IgV domain and an immunoreceptor tyrosine-based domain. TIGIT was found to be upregulated in tumor antigen-specific CD8+ T-cells and CD8+ TILs involved in adaptive immune tumor surveillance. TIGIT is also expressed on NK cells, and its binding directly inhibits NK cytotoxicity. This downregulation of NK cell activity is achieved by the phosphorylation of immunoreceptor tail tyrosine (ITT)-like domain of the cytoplasmic tail of TIGIT.

The adhesion molecule CD155, also known as poliovirus receptor (PVR) or NECL5, serves as a high-affinity ligand for TIGIT binding. CD155 is highly expressed on dendritic cells (DCs), monocytes, endothelial cells, fibroblasts, epithelial cells, platelets, and activated T cells and B cells. By contrast, CD112 (nectin-2, also known as PVRL2 or PRR2) is a low-affinity ligand for TIGIT binding and also expressed on monocytes, DCs, hematopoietic cells, endothelial cells, and activated T cells and B cells. Aside from TIGIT, CD112 and CD155 also bind to other ligands including the co-stimulatory counterparts to TIGIT, such as CD96 or CD226, which act in concert with lymphocyte function-associated antigen 1 (LFA-1) to positively modulated T-cell responses.

The Role of TIGIT in Immune Biology

Similar to the inhibitory receptors CTLA-4 and PD-1, TIGIT has also been shown to be important in autoimmunity. In contrast to mice deficient for CTLA-4, TIGIT^-/- mice that are not immune-challenged do not develop immune pathologies, indicating that TIGIT may not be crucial for acute T cell priming. TIGIT^-/- mice or anti-TIGIT blocking antibodies also resulted in more severe autoimmunity in graft-versus-host disease and collagen-induced arthritis model. TIGIT-Fc was able to inhibit delayed-type hypersensitivity responses in mice, confirming TIGIT as an important inhibitory immunoreceptor. The kinetics of expression for CD226/TIGIT are similar to those of CD28/CTLA-4, with the costimulatory receptor being expressed on naïve and resting T cells and the coinhibitory receptor being expressed following T cell activation. TIGIT is weakly expressed or absent on naïve cells but can be rapidly induced by antigenic and other inflammatory stimuli. In this regard, the characteristics of TIGIT make it attractive as a target for immunotherapy.

TIGIT and Tumor Immunity

Because of its broad expression on lymphocytes, TIGIT has become an important immune checkpoint capable of inhibiting each step of the cancer immunity circle. TIGIT can prevent tumor antigen release by NK cells, impair T cell priming by DCs or inhibit cancer cell killing by CD8+ T cells. CD112 and CD155, ligands of TIGIT, have been found to be expressed by various human tumors besides immune cells, indirectly suggesting the involvement of TIGIT in tumor immunity. Besides, Fusobacterium nucleatum is a commonly observed anaerobic Gram-negative rod in tumor microenvironment, which contains an element for human TIGIT binding. Fap2 protein is the key element for the interaction of Fusobacterium nucleatum with TIGIT, and thus identified as the bacterial ligand for human TIGIT. Binding of Fap2 protein to TIGIT triggers negative signals and inhibits the activities of NK cells and T cells, thereby protecting tumors from immune cell attack. This study is of clinical importance as it reveals a novel mechanism of how bacteria participate in tumor immune evasion.

Figure 1. T cell immunoglobulin and ITIM domain (TIGIT) in the cancer-immunity cycle. (Harjunpää H, Guillerey C., 2020)

Recently, some groups reported consistently that TIGIT was highly expressed on CD8+ TILs in different types of tumors. Johnston et al. suggested that the antibody blockade of TIGIT and PD-L1 synergistically and specifically enhanced effector function of CD8+ T cells, resulting in remarkably increased tumor rejection. This effect could be eliminated by blockade of the TIGIT's complementary co-stimulatory receptor, CD226, whose homodimerization was directly disrupted upon TIGIT interaction. In addition to TIGIT upregulation, Chauvin et al. also observed a considerable decrease in CD226 expression of CD8+ TILs in human melanoma, suggesting a TIGIT/CD226 imbalance in tumor progression. They also found that dual blockade of TIGIT and PD-1 could significantly elicit antitumor CD8+ T-cell responses. On the contrary, another study exhibited that TIGIT signaling dictated Treg phenotypes and TIGIT primary suppressed antitumor immunity through Tregs instead of CD8+ T cells. All these data indicate that aberrant TIGIT expression contributes greatly to tumor immune escape.

References:

Manieri N A, et al. TIGIT: a key inhibitor of the cancer immunity cycle. Trends in immunology, 2017, 38(1): 20-28.
Solomon B L, Garrido-Laguna I. TIGIT: a novel immunotherapy target moving from bench to bedside. Cancer Immunology, Immunotherapy, 2018, 67(11): 1659-1667.
Dougall W C, et al. TIGIT and CD 96: new checkpoint receptor targets for cancer immunotherapy. Immunological reviews, 2017, 276(1): 112-120.
Liu X, et al. TIGIT, a novel therapeutic target for tumor immunotherapy. Immunological investigations, 2017, 46(2): 172-182.
Kurtulus S, et al. Mechanisms of TIGIT-driven immune suppression in cancer. Journal for ImmunoTherapy of Cancer, 2014, 2(S3): O13.
Harjunpää H, Guillerey C. TIGIT as an emerging immune checkpoint. Clinical & Experimental Immunology, 2020, 200(2): 108-119.

Quick Inquiry

Interested in learning more?

Contact us today for a free consultation with the scientific team and discover how Creative Biogene can be a valuable resource and partner for your organization.

Request a quote today!

Inquiry