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TIGIT: A New Frontier in Cancer and Autoimmune Disease Immunotherapy

TIGIT: A New Frontier in Cancer and Autoimmune Disease Immunotherapy

TIGIT (T cell immunoreceptor with Ig and ITIM domains) has emerged as a promising target in cancer immunotherapy and the treatment of autoimmune diseases. As a checkpoint receptor, TIGIT plays a critical role in regulating immune responses by inhibiting the activity of immune cells, especially T cells and natural killer (NK) cells. By manipulating TIGIT pathways, scientists aim to develop therapies that enhance immune responses against cancer or dampen harmful immune activity in autoimmune disorders.


Understanding TIGIT's Role in Immune Regulation


TIGIT belongs to the immunoglobulin superfamily and is primarily expressed on T cells, including regulatory T cells (Tregs), activated T cells, and natural killer (NK) cells. The activation of TIGIT inhibits the immune system's ability to attack cancer cells or viruses, making it an ideal target for immunotherapies aimed at boosting anti-tumor immunity.

TIGIT interacts with ligands like CD155 (PVR) and CD112 (Nectin-2) on antigen-presenting cells (APCs), leading to an immune-suppressive signal. This interaction can modulate immune cell activity in different ways:

By blocking TIGIT, therapies can potentially reverse these suppressive effects, leading to enhanced immune responses against tumors or balancing autoimmune reactions.



TIGIT in Cancer Immunotherapy


In the context of cancer, tumors often exploit immune checkpoint pathways like TIGIT to evade the immune system. Tumor cells upregulate TIGIT ligands such as CD155, which bind to TIGIT on T cells, preventing these immune cells from attacking the tumor. Blocking TIGIT has shown promise in preclinical models and early clinical trials as it can restore the immune system's ability to destroy cancer cells.


Table 1: TIGIT Blockade in Clinical Trials for Cancer Immunotherapy

Cancer Type

TIGIT-Targeting Therapy

Clinical Trial Phase

Observed Outcomes

Non-Small Cell Lung Cancer (NSCLC)In 

Phase II

Improved progression-free survival when combined with anti-PD-L1 therapies

Melanoma

Ociperlimab (anti-TIGIT mAb)

Phase I/II

Enhanced T cell activation and tumor regression

Colorectal Cancer

Phase I

Ongoing trials, preliminary signs of efficacy

Head and Neck Squamous Cell Carcinoma

Phase II

Combination with pembrolizumab shows potential synergy


The combination of TIGIT inhibitors with other immune checkpoint therapies, such as anti-PD-1 and anti-CTLA-4, has been particularly encouraging. By simultaneously targeting multiple immune checkpoints, these therapies may overcome the various mechanisms tumors use to suppress immune responses, leading to better clinical outcomes.


TIGIT in Autoimmune Diseases

Autoimmune diseases are characterized by an overactive immune response that targets the body's own tissues. In contrast to cancer, where blocking TIGIT enhances immune responses, activating TIGIT can suppress the excessive immune activity seen in autoimmune disorders.


In diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA), TIGIT expression is increased on Tregs, which are crucial for maintaining immune tolerance. Therapeutic strategies aimed at boosting TIGIT activity or mimicking its effects may help restore the immune balance in these diseases.


Table 2: Role of TIGIT in Autoimmune Diseases

Autoimmune Disease

TIGIT Expression

Potential Therapeutic Approach

Research Status

Increased on Tregs

TIGIT agonists or mimetics

Preclinical research, early trials

Upregulated on effector T cells

TIGIT activation to suppress immune response

Early preclinical investigations

Low levels on CD8+ T cells

Enhance TIGIT to restore tolerance

Ongoing research


Therapies aimed at modulating TIGIT in autoimmune diseases are still in the early stages. However, initial results suggest that TIGIT agonists or mimetic drugs could dampen harmful immune responses and prevent further tissue damage.


Mechanisms of Action: TIGIT vs. PD-1 and CTLA-4

TIGIT is often compared to other immune checkpoints such as PD-1 and CTLA-4, both of which have been successfully targeted in cancer immunotherapy. However, these pathways operate through distinct mechanisms, which can be complementary in combination therapies.


Table 3: Comparison of TIGIT, PD-1, and CTLA-4 Mechanisms

Checkpoint Receptor

Primary Function

Ligands

Mechanism of Immunosuppression

Inhibits
T and NK cells

Suppresses immune cell proliferation, decreases cytokine secretion

Inhibits T cell activation

Reduces T cell effector function, induces T cell exhaustion

Dampens early T cell responses

Blocks co-stimulatory signals required for T cell activation


Combining TIGIT blockade with PD-1 inhibitors or CTLA-4 inhibitors may yield synergistic effects by activating T cells at multiple stages of immune response regulation, improving anti-tumor efficacy.


Challenges and Future Directions

While TIGIT has shown considerable potential, several challenges remain:


  • Patient-specific responses: Not all patients respond equally to TIGIT-targeted therapies, raising the need for biomarkers that can predict who will benefit the most.

  • Immune-related side effects: Overactivation of the immune system, particularly when combined with other checkpoint inhibitors, can lead to immune-related adverse events (irAEs), such as inflammation of healthy tissues.

  • Long-term efficacy: More data are needed to determine how long the beneficial effects of TIGIT blockade last and whether resistance mechanisms may emerge.

Future Research Areas


  • Biomarker discovery:
    Identifying reliable biomarkers for patient selection will be crucial for improving clinical outcomes.

  • Combination therapies:
    Exploring TIGIT's interaction with other immune checkpoints and immunecells could reveal new combination strategies.

  • Autoimmune disease applications: Developing TIGIT-based therapies for autoimmuneconditions is still in its infancy, but offers a promising research direction.

Conclusion


TIGIT represents a significant new frontier in the field of immunotherapy for both cancer and autoimmune diseases. By targeting TIGIT, researchers hope to fine-tune immune responses, either enhancing them to fight cancer or suppressing them to treat autoimmune diseases. The development of TIGIT-based therapies holds great potential, but further research is essential to address existing challenges and optimize their clinical application.


References

1st Oct 2024 Sana Riaz

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