Advances in Immune Checkpoint TIGIT in Tumors

As a receptor of the immunoglobulin superfamily, TIGIT participates in immunosuppression by inhibiting the function of immune cells and causing tumor immune escape. The application of TIGIT antibodies for tumor treatment shows great promise in tumor immunotherapy. Currently, pharmaceutical companies around the world have developed a series of drugs targeting TIGIT, including TIGIT monoclonal antibodies and PD-1/TIGIT dual antibodies.

Creative Biolabs provides an overview of TIGIT expression, molecular structure and signaling pathways, immunoregulatory mechanisms, and the development of new drugs.

TIGIT and Its Ligands

TIGIT is highly expressed in CD8⁺ T cells from a variety of solid tumors, and TIGIT-expressing CD8⁺ T cells also express high levels of PD-1, as well as other immune checkpoints, such as TIM-3 and LAG-3. The expression of CD226, an immune-activating receptor that competes with TIGIT for CD155, is decreased.

• TIGIT has a higher affinity for CD155 than its competing receptors CD226 and CD96.
• TIGIT-bound CD155 triggers the internalization and degradation of CD226, leading to reduced NK cell-mediated tumor-killing activity.

Mechanisms of Immunomodulatory Action of TIGIT

TIGIT is involved in a complex regulatory network involving multiple inhibitory receptors such as CD96 and CD112R, competitive co-stimulatory receptor such as CD226, and multiple ligands such as CD155, CD112. Inhibitory receptors and co-stimulatory receptors compete for binding to the same ligand.

• TIGIT/CD155 exerts direct or indirect immunosuppressive effects. TIGIT exerts immunosuppressive effects on T cells indirectly by binding to CD155 on DCs and modulating cytokines produced by DCs.
• TIGIT antagonizes CD226-mediated costimulatory signaling. TIGIT indirectly induces T cell exhaustion by competing with the costimulatory receptor CD226 for CD155.
• TIGIT stimulates Treg to produce cytokines that inhibit T cell proliferation.

Preclinical Studies of TIGIT Antibody

It has been found that blocking TIGIT with a monoclonal antibody reverses the depletion of anti-tumor NK cells in a variety of tumor models, while blocking TIGIT in an NK cell-dependent manner also leads to potent tumor-specific T cell immunity.

• A study in a mouse model of B16 melanoma and CT26 lung metastases showed that TIGIT antibody alone or in combination with PD-1 antibody prevented tumor growth by enhancing the antitumor effect of CD8⁺ T cells.
• Some researchers have found that TIGIT is overexpressed on tumor-infiltrating CD8⁺ and CD4⁺ T cells and correlates with the expression of the immune checkpoint molecule PD-1 in patients and in a mouse model with head and neck squamous cell carcinoma (HNSCC).
• In an analysis of the immune checkpoints associated with small cell lung cancer (SCLC), some researchers found that co-expression of TIGIT and PD-1 was detected on the surface of CD8⁺ TILs.
• The researchers treated CT26 model mice with colon cancer with anti-TIGIT and anti-PD-1 antibodies alone or in combination and found that blockade with anti-TIGIT or anti-PD-1 antibodies alone was not sufficient to inhibit tumor growth, whereas dual anti-PD-1/TIGIT antibodies significantly inhibited tumor growth.
• TIGIT antibody and TIM-3 antibody could synergistically inhibit tumor immune escape in mice by restoring T cell function through enhancing CD8⁺ T cell growth, proliferation and cytokine production.

Thus, targeting TIGIT alone or in combination with other immune checkpoint antibodies is a promising antitumor therapeutic strategy.

Current Status of Clinical Research on TIGIT Antibody

Shortly after the discovery of TIGIT, clinical studies of drugs targeting this immunotherapeutic checkpoint were initiated. Currently, more than 10 anti-TIGIT antibodies are in clinical trials, but no drugs targeting this immune checkpoint have been approved for marketing worldwide.

• Anti-TIGIT antibody drug binds to TIGIT and blocks its interaction with the ligand CD155. Currently, two Phase III clinical trials have been initiated to evaluate the therapy in patients with non-small cell lung cancer (NSCLC) and extensive small cell lung cancer (ES-SCLC).
• An anti-TIGIT drug candidate is currently in Phase II clinical trials.
• Studies of an antibody drug that targets TIGIT to evaluate the safety and efficacy of therapies for patients with solid tumors are currently underway.

An in-depth study of the mechanisms of TIGIT-mediated immune response modulation will help optimize the combination of TIGIT blockers with other immune checkpoint blockers for cancer patients. Creative Biolabs will help scientists design ideal TIGIT-based therapeutic strategies.

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