The TIGIT protein, or T-cell immunoreceptor with Ig and ITIM domains, is a component of the immune system. Found on the surface of T cells and natural killer (NK) cells, TIGIT functions like a “checkpoint” or “switch” to regulate immune responses.
TIGIT as an Immune System Regulator
TIGIT operates as an inhibitory receptor, meaning it inhibits immune cell activity. When TIGIT binds to its specific ligands, such as CD155 (PVR) and CD112 (Nectin-2), it sends signals that suppress the immune response. This interaction primarily affects T cells and NK cells, reducing their activation and proliferation.
This inhibitory role maintains immune balance and prevents overreaction. By dampening immune cell activity, TIGIT helps protect healthy tissues from damage. The balance between TIGIT’s inhibitory signals and activating signals from other receptors, like CD226, is essential for proper immune regulation.
TIGIT’s Involvement in Cancer
Cancer cells often take advantage of TIGIT to escape detection and destruction by the immune system. TIGIT expression can be elevated on immune cells within the tumor’s microenvironment. This increased TIGIT activity suppresses the anti-tumor immune response, allowing cancer to grow.
When TIGIT on immune cells binds to its ligands, CD155 and CD112, on tumor cells or antigen-presenting cells, it triggers inhibitory signals. This reduces the activation, proliferation, and cytotoxicity of T cells and NK cells. This process can contribute to “immune exhaustion,” where T cells become dysfunctional and lose their ability to effectively combat the tumor.
TIGIT contributes to the progression of various cancers. High TIGIT expression on tumor-infiltrating T cells has been observed in melanoma, lung cancer, and colorectal cancer, often correlating with poorer patient outcomes. In colorectal cancer, TIGIT-expressing CD8+ T cells exhibit features of exhaustion, including reduced production of cytokines like IFN-γ, IL-2, and TNF-α.
TIGIT’s Role in Autoimmune Conditions
While TIGIT primarily suppresses immune responses, its dysregulation can also contribute to autoimmune diseases. An imbalance or dysfunction in TIGIT’s inhibitory role might lead to unchecked immune activity.
Research indicates that enhancing TIGIT’s function can protect against autoimmune or inflammatory diseases. Conversely, blocking the TIGIT pathway has been shown to worsen several autoimmune conditions in mouse models. This suggests that manipulating the TIGIT pathway could lead to treatments for autoimmune disorders by restoring immune tolerance and inhibiting autoreactive T cells.
Developing Therapies That Target TIGIT
Understanding TIGIT’s role has led to the development of therapeutic strategies aimed at modulating its activity for cancer treatment. TIGIT-blocking antibodies are designed to “release the brakes” on the immune system, allowing it to more effectively fight cancer. These therapies work by preventing TIGIT from binding to its ligands, thereby enhancing the anti-tumor immune response.
TIGIT inhibitors aim to boost the activation and proliferation of T cells and NK cells. They can also reduce the suppressive activity of regulatory T cells, which often contribute to the immune-suppressing environment within tumors.
TIGIT inhibitors are frequently explored in combination with other immune checkpoint inhibitors, such as PD-1/PD-L1 blockers, for enhanced efficacy. This dual blockade has shown promise in preclinical studies by enhancing T-cell mediated effects and promoting tumor rejection. Over 50 anti-TIGIT antibodies are currently in clinical development, with several in advanced phases, indicating strong interest in this therapeutic approach for various cancer types.