TIGIT: A Crucial Immune Checkpoint for Melanoma

The immune system identifies and eliminates cancer cells, but tumors develop ways to evade detection. One method involves immune checkpoints—molecules that regulate immune responses to prevent excessive damage to healthy tissues. While these checkpoints maintain balance, cancers exploit them to suppress immune attacks.

TIGIT is an inhibitory receptor that dampens anti-tumor immunity. Its role in immune regulation makes it a critical target in cancer research, particularly in melanoma, where immune evasion affects disease progression and treatment outcomes.

Mechanisms Of This Immune Checkpoint

TIGIT modulates immune activity by interacting with ligands CD155 and CD112, expressed on antigen-presenting and tumor cells. This interaction transmits a suppressive signal, reducing the proliferation and cytotoxicity of T cells and natural killer (NK) cells. Structurally, TIGIT contains an immunoglobulin variable (IgV) domain that facilitates ligand binding, leading to downstream signaling that interferes with immune function. Unlike activating receptors such as CD226, which promote immune responses, TIGIT engagement recruits inhibitory pathways that favor immune tolerance.

TIGIT’s suppressive effects involve intracellular signaling mechanisms. Upon ligand binding, TIGIT recruits the phosphatase SHP-2, which dephosphorylates signaling molecules involved in T cell receptor (TCR) activation. This reduces ZAP-70 phosphorylation, impairing cytokine production and immune synapse formation. Additionally, TIGIT signaling enhances FoxP3 expression, reinforcing the suppressive function of regulatory T cells (Tregs). This dual mechanism—direct inhibition of effector T cells and reinforcement of immunosuppressive Tregs—creates an environment favoring immune tolerance.

Beyond T cells, TIGIT suppresses NK cell function by interfering with their ability to eliminate malignant cells. NK cells rely on a balance of activating and inhibitory signals to determine whether to mount an attack. TIGIT engagement inhibits NK cell cytotoxicity by reducing granzyme B and perforin secretion, essential for inducing apoptosis in target cells. It also downregulates activating receptors such as NKp46 and NKG2D, further impairing NK cell-mediated tumor clearance. This suppression is particularly relevant in melanoma, where NK cells help control tumor progression.

Inducible Expression In T Cells And NK Cells

TIGIT expression is dynamically regulated in response to immune activation in T cells and NK cells. Under basal conditions, it is low on naïve and resting immune cells but upregulated upon antigenic stimulation. This inducibility is driven by T cell receptor (TCR) signals in CD4⁺ and CD8⁺ T cells and cytokine-mediated activation in NK cells. Interleukin-2 (IL-2) and interleukin-15 (IL-15), which promote immune cell proliferation, enhance TIGIT expression through STAT5-dependent mechanisms. This suggests TIGIT acts as a feedback mechanism to modulate excessive immune activity.

Epigenetic modifications also regulate TIGIT expression. DNA methylation patterns in the TIGIT promoter influence transcriptional accessibility, with hypomethylation correlating with increased expression in activated T cells. Histone modifications such as H3K27 acetylation further promote TIGIT transcription. These regulatory mechanisms ensure that TIGIT expression adjusts to environmental cues. In tumor-infiltrating lymphocytes (TILs), chronic antigen exposure sustains TIGIT expression. Studies of melanoma patients’ TILs show significantly higher TIGIT levels compared to peripheral blood lymphocytes, highlighting the tumor microenvironment’s role in maintaining its expression.

In NK cells, TIGIT upregulation follows a similar pattern, with activation-induced expression occurring in response to inflammatory cytokines and receptor engagement. IL-12 and IL-18, which enhance NK cell cytotoxicity, also increase TIGIT levels, suggesting its expression is part of a broader regulatory network. TIGIT expression in NK cells is often linked to an exhausted phenotype, characterized by diminished function and reduced interferon-gamma (IFN-γ) production. This exhaustion is pronounced in chronic disease settings, where persistent antigen stimulation leads to functional decline. In melanoma, NK cells with high TIGIT expression exhibit impaired degranulation and reduced tumor-targeting ability, reinforcing its role in modulating immune responses.

Tumor Immune Evasion Through TIGIT

Melanoma cells exploit TIGIT to weaken immune surveillance, making immune cells less effective at eliminating malignancies. One way this occurs is through the upregulation of TIGIT ligands, particularly CD155, on tumor cells and surrounding stromal components. Elevated CD155 expression in melanoma biopsies correlates with advanced disease stages. This overexpression enhances TIGIT-mediated suppression, reinforcing an immunosuppressive network that weakens anti-tumor responses. The tumor microenvironment further amplifies this effect by producing immunoregulatory cytokines such as transforming growth factor-beta (TGF-β), which sustains the expression of TIGIT and its ligands, deepening immune dysfunction.

The metabolic landscape within the tumor also sustains TIGIT-driven immune evasion. Melanoma cells deplete essential nutrients like glucose and tryptophan while accumulating immunosuppressive metabolites such as adenosine and kynurenine. These metabolic shifts reinforce TIGIT signaling by impairing immune cell metabolism, reducing energy availability, and limiting effector function. Hypoxia, a common feature of solid tumors, exacerbates this suppression by stabilizing hypoxia-inducible factor-1 alpha (HIF-1α), which increases TIGIT expression in tumor-infiltrating immune cells. This metabolic reprogramming ensures immune cells remain dysfunctional.

TIGIT also facilitates immune evasion by disrupting communication between immune cells. In melanoma, TIGIT-expressing regulatory T cells (Tregs) suppress nearby effector T cells through cell-contact-dependent mechanisms, including inhibitory signals via gap junctions and secretion of immunosuppressive cytokines such as interleukin-10 (IL-10). TIGIT engagement impairs dendritic cell maturation, reducing their ability to present tumor antigens. This weakens tumor-specific immune responses, allowing melanoma cells to evade detection.

Relevance In Melanoma

TIGIT is emerging as a biomarker for melanoma progression and therapeutic resistance. Clinical studies show elevated TIGIT expression in melanoma patients, particularly those with advanced or treatment-refractory disease. High TIGIT levels in circulating and tumor-infiltrating lymphocytes correlate with poorer responses to immune checkpoint inhibitors (ICIs) like anti-PD-1 and anti-CTLA-4 therapies, suggesting TIGIT contributes to resistance mechanisms that limit treatment efficacy. This has led to growing interest in TIGIT-targeted therapies, with several monoclonal antibodies under investigation.

The therapeutic landscape for melanoma has evolved with immune-based treatments, yet many patients fail to achieve durable responses. TIGIT blockade is being explored as a way to restore immune function in those who do not respond to existing ICIs. Early-phase clinical trials evaluating TIGIT inhibitors, such as tiragolumab in combination with anti-PD-1 therapy, show promise in improving response rates, particularly in highly immunosuppressive tumor environments. Combination strategies aim to target multiple inhibitory pathways, enhancing the immune system’s ability to eliminate melanoma cells while minimizing immune exhaustion.