TIGIT Axis: Immune Checkpoint & Cancer Therapy
The TIGIT axis is an immune checkpoint pathway that regulates T cell activity and plays a key role in cancer and autoimmune diseases.
Things worth knowing about "TIGIT Axis"
The TIGIT axis is an immune checkpoint pathway that regulates T cell activity and plays a key role in cancer and autoimmune diseases.
What Is the TIGIT Axis?
The TIGIT axis refers to an immunological signaling network centered around the receptor TIGIT (T cell Immunoreceptor with Ig and ITIM domains). TIGIT is an inhibitory receptor expressed on the surface of T lymphocytes and natural killer (NK) cells. Together with its ligands and related receptors, it forms a regulatory axis that controls immune system activity. The TIGIT axis belongs to the group of so-called immune checkpoints – biological brakes of the immune system that normally prevent overactivation but can undesirably suppress immune responses in the context of cancer or chronic infections.
Components of the TIGIT Axis
The TIGIT axis involves several interacting molecules:
- TIGIT: The central inhibitory receptor on T cells and NK cells.
- CD226 (DNAM-1): An activating receptor that competes with TIGIT for the same ligands, exerting the opposite, stimulatory effect on immune cells.
- CD112 (Nectin-2) and CD155 (PVR, Poliovirus Receptor): The main ligands of the TIGIT axis, expressed on tumor cells, dendritic cells, and other tissue cells.
- CD96 and CD112R (PVRIG): Additional inhibitory receptors that bind the same ligands and can further reinforce immunosuppression.
The balance between inhibitory TIGIT and activating CD226 determines whether an immune cell is activated or suppressed.
Mechanism of Action
When TIGIT binds to its ligands CD155 or CD112, it triggers intracellular signaling cascades that inhibit T cell activation. This occurs through several mechanisms:
- Direct inhibition: TIGIT transmits inhibitory signals into the T cell via its intracellular ITIM domain (Immunoreceptor Tyrosine-based Inhibitory Motif).
- Competition with CD226: Because TIGIT has a higher binding affinity for CD155 than CD226, it displaces the activating receptor and thereby reduces activating signals.
- Indirect inhibition via dendritic cells: Binding of TIGIT to CD155 on dendritic cells promotes secretion of the anti-inflammatory cytokine IL-10 while suppressing pro-inflammatory cytokines such as IL-12, thereby broadly dampening the immune response.
- Promotion of regulatory T cells: TIGIT is highly expressed on regulatory T cells (Tregs) and enhances their immunosuppressive function.
Relevance in Cancer
Tumor cells frequently overexpress the TIGIT ligands CD155 and CD112 to shield themselves from recognition and destruction by the immune system. By generating an immunosuppressive tumor microenvironment through TIGIT engagement, cancer cells can evade immune surveillance – a process known as immune evasion. Overexpression of CD155 has been documented in many tumor types, including lung, colorectal, liver, and cervical cancer as well as hematological malignancies, and is associated with poorer patient outcomes.
Therapeutic Approaches: TIGIT Inhibitors
Blocking the TIGIT axis represents a promising strategy in immune checkpoint therapy. By using anti-TIGIT antibodies, the artificial brake on the immune system can be released, enabling T cells and NK cells to effectively target and eliminate tumor cells again.
Key Compounds in Clinical Development
- Tiragolumab: An anti-TIGIT antibody developed by Roche/Genentech, being investigated in combination with the PD-L1 inhibitor atezolizumab in multiple Phase II and Phase III trials.
- Domvanalimab: Another anti-TIGIT antibody (Arcus Biosciences) being tested in combination with PD-1 inhibitors.
- Vibostolimab: Developed by MSD, studied in combination with pembrolizumab.
Combination Strategies
Because TIGIT and PD-1/PD-L1 exploit distinct, complementary mechanisms of immunosuppression, combined blockade of both axes promises a synergistic therapeutic effect. Many ongoing clinical trials are therefore evaluating anti-TIGIT antibodies in combination with already approved PD-1 or PD-L1 inhibitors such as pembrolizumab or atezolizumab.
TIGIT Axis in Other Diseases
Beyond oncology, the TIGIT axis also plays a role in other conditions:
- Chronic viral infections: Elevated TIGIT expression on exhausted T cells has been observed in HIV, hepatitis B and C, and SARS-CoV-2 infection, contributing to viral persistence.
- Autoimmune diseases: Since TIGIT dampens immune responses, stimulating the TIGIT axis could theoretically be harnessed therapeutically in autoimmune conditions to restore immune tolerance.
References
- Johnston RJ et al. - The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function. Cancer Cell, 2014. PubMed PMID: 24856585.
- Chauvin JM, Zarour HM - TIGIT in cancer immunotherapy. Journal for ImmunoTherapy of Cancer, 2020. DOI: 10.1136/jitc-2020-000957.
- Manieri NA et al. - TIGIT: A Key Inhibitor of the Cancer Immunity Cycle. Trends in Immunology, 2017. DOI: 10.1016/j.it.2016.10.002.
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