TIGIT: A Key Player in Cancer Immunotherapy

TIGIT, or T-cell immunoreceptor with immunoglobulin and ITIM domain, is an inhibitory immune checkpoint receptor that has recently gained attention for its role in modulating immune responses, especially within the tumor microenvironment (TME). Targeting TIGIT has emerged as a promising therapeutic strategy in cancer immunotherapy due to its effects on T-cells, NK cells, and regulatory T-cells (Tregs). Here, we provide an overview of TIGIT, its history, function, and potential as a therapeutic target.

History of TIGIT Discovery

TIGIT was first discovered in 2009 through genome-wide analyses aimed at identifying immunoregulatory receptors. Research efforts identified TIGIT as a member of the immunoglobulin superfamily, with unique structural and signaling domains suited for inhibitory functions. Since its discovery, TIGIT has been a focus in immuno-oncology research, as studies have linked its activity with immune suppression in cancer, particularly through its interaction with the ligand CD155.^1,2

What Does TIGIT Stand For?

TIGIT stands for T cell immunoreceptor with immunoglobulin and ITIM domain. This name reflects TIGIT’s structural composition: an extracellular immunoglobulin domain and an intracellular ITIM (immunoreceptor tyrosine-based inhibitory motif) domain, which plays a critical role in delivering inhibitory signals to immune cells.¹

What Do TIGIT Proteins Do?

TIGIT functions as an immune checkpoint receptor that regulates immune cell activity in the TME. It is primarily expressed on several lymphocyte subsets, including CD8 T cells, CD4 T cells including Tregs, and NK cells. TIGIT acts by binding to ligands including CD155, Nectin-2 and Nectin-4 which are often overexpressed on tumor cells. This binding sends an inhibitory signal to immune cells, suppressing their cytotoxic activity and promoting immune tolerance within tumors. TIGIT’s role as an immune checkpoint helps the immune system to avoid overactivation, which can prevent autoimmune responses but also allows cancer cells to evade immune surveillance.^1,2,3

TIGIT Structure and Signaling Pathways

TIGIT is a Type I integral membrane protein. The structure of TIGIT includes an extracellular immunoglobulin variable (IgV) domain, a transmembrane domain, and a cytoplasmic tail with two key motifs: the ITIM and an immunoglobulin tail-tyrosine (ITT)-like motif. TIGIT extracellular domain (ectodomain, ECD) interacts with its ligands. Upon binding to its ligands, TIGIT initiates inhibitory signaling through phosphorylation at these motifs, which leads to downstream effects such as reduced production of proinflammatory cytokines and decreased cytotoxic activity in NK and T-cells. The signaling pathways involved in TIGIT activity often intersect with other immune checkpoints like PD-1, forming complex regulatory networks that maintain immune homeostasis but also contribute to immune evasion by tumors.^3,4 TIGIT can form homodimers on the cell membrane. The dimerization could alter the binding affinity for ligands including CD155 and Nectin-4, potentially increasing its immunosuppressive activity.

Role of TIGIT in Disease

TIGIT and Cancer

TIGIT expression is typically low in naive immune cells but is upregulated in T-cells and NK cells upon activation. In the context of cancer, TIGIT expression increases in tumor-infiltrating lymphocytes (TILs) as a response to chronic antigen exposure. This overexpression is associated with T-cell exhaustion, a state in which T-cells lose their ability to effectively combat tumor cells. Furthermore, TIGIT’s ligands like CD155, Nectin-2 and Nectin-4, are often overexpressed in various cancers, enhancing TIGIT-mediated immune suppression and contributing to tumor progression. Dual blockade of TIGIT and PD-1 has shown promise in preclinical and early clinical studies, particularly in enhancing CD8+ T-cell activity and NK cell function.^2,3

TIGIT and Autoimmune Disorders

While TIGIT’s primary role in the context of cancer immunotherapy is its immune-inhibitory effect, studies in autoimmune disease models have shown that TIGIT can help prevent excessive immune responses that could lead to tissue damage. For instance, in autoimmune encephalitis models, TIGIT-deficient mice exhibit more severe disease, highlighting TIGIT’s role as a negative regulator of immune responses. This duality underscores the therapeutic challenge of targeting TIGIT in diseases where immune balance is critical.³

Therapeutic Potential of Targeting TIGIT

In cancer therapy, TIGIT has emerged as an important target for immune checkpoint inhibition. Single-agent TIGIT blockade has shown limited efficacy in preclinical models, but when combined with PD-1 inhibitors, the anti-tumor response is significantly enhanced. This synergy is due in part to TIGIT’s role in both adaptive and innate immunity, as TIGIT inhibition boosts not only T-cell responses but also NK-cell cytotoxicity against tumor cells.

Current clinical trials are investigating the effects of dual blockade strategies that target both TIGIT and PD-1 pathways. Preliminary results indicate that this approach may be particularly effective in PD-1-resistant tumors. Moreover, TIGIT inhibition has demonstrated a unique benefit compared to CTLA-4 inhibitors by showing fewer severe immune-related adverse effects.^1,2,3

Expression of TIGIT in Immune Cells

TIGIT is expressed on multiple immune cells, including:

CD8+ and CD4+ T cells: Especially tumor-specific CD8+ T-cells in the TME, where co-expression of PD-1 and TIGIT indicates an exhausted T-cell state.

NK cells: TIGIT is expressed on NK cells and is associated with higher cytotoxic potential; however, in the TME, its activity is paradoxically inhibitory due to competition for CD155 with CD226, an activating receptor.

Regulatory T cells (Tregs): In cancer, TIGIT+ Tregs are particularly suppressive and contribute to immune tolerance within the tumor environment.^2,4

Key Questions and Future Directions

1. How can TIGIT blockade best be combined with other checkpoint inhibitors?
   Combining TIGIT blockade with PD-1 or PD-L1 inhibition has shown the most promise, with ongoing trials exploring this combination across different cancer types.
2. What is the impact of TIGIT on innate immunity, particularly NK cells?
   Unlike other checkpoint molecules, TIGIT plays a significant role in regulating NK-cell activity in tumors. TIGIT inhibition in NK cells could open additional therapeutic avenues beyond T-cell-focused therapies.³
3. Can TIGIT inhibition reduce the immune suppressive capacity of Tregs?
   Studies indicate that blocking TIGIT on Tregs can decrease their suppressive function, thus potentially boosting overall antitumor immunity in the TME.⁴

Conclusion

TIGIT represents an innovative and complex target in cancer immunotherapy. Its ability to modulate both adaptive and innate immune responses makes it unique among checkpoint inhibitors, offering new opportunities in combination therapies for cancer treatment. As research progresses, understanding TIGIT’s monomeric and dimeric molecule interactions with its ligands within the immune checkpoint network will be essential to developing more effective, targeted treatments that maximize therapeutic benefits while minimizing adverse effects.

To mimic the TIGIT homodimer on the cell surface, three forms of cis-homodimer proteins are designed and generated by Conigen with Fc tag, His-tag, or His-tag+Avitag fused at the C-terminus.  These TIGIT cis-homodimer proteins are bioactive in binding to ligands CD155, and Nectin-4.  These innovative TIGIT dimer proteins can be used for drug discovery and basic research, as immunogen/antigen to generate specific antibodies targeting the natural dimer and study the TIGIT and ligand interactions.

References

1. Zhang, P., Liu, X., Gu, Z., Jiang, Z., Zhao, S., Song, Y., & Yu, J. (2024). Targeting TIGIT for cancer immunotherapy: recent advances and future directions. Biomarker Research, 12(7). https://doi.org/10.1186/s40364-023-00543-z.
2. Harjunpää, H., & Guillerey, C. (2019). TIGIT as an emerging immune checkpoint. Clinical and Experimental Immunology, 200(2), 108-119. https://doi.org/10.1111/cei.13407.
3. Chauvin, J.-M., & Zarour, H. M. (2020). TIGIT in cancer immunotherapy. Journal for ImmunoTherapy of Cancer, 8(2), e000957. https://doi.org/10.1136/jitc-2020-000957.
4. Ge, Z., Peppelenbosch, M. P., Sprengers, D., & Kwekkeboom, J. (2021). TIGIT, the Next Step Towards Successful Combination Immune Checkpoint Therapy in Cancer. Frontiers in Immunology, 12, 699895. https://doi.org/10.3389/fimmu.2021.699895.