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:

Inhibiting T cell proliferation

Reducing cytokine secretion

Suppressing NK cell-mediated cytotoxicity

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	Tiragolumab (anti-TIGIT mAb)	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	Tiragolumab	Phase I	Ongoing trials, preliminary signs of efficacy
Head and Neck Squamous Cell Carcinoma	Vibostolimab	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
Multiple Sclerosis (MS)	Increased on Tregs	TIGIT agonists or mimetics	Preclinical research, early trials
Rheumatoid Arthritis (RA)	Upregulated on effector T cells	TIGIT activation to suppress immune response	Early preclinical investigations
Type 1 Diabetes (T1D)	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
TIGIT	Inhibits T and NK cells	CD155, CD112	Suppresses immune cell proliferation, decreases cytokine secretion
PD-1	Inhibits T cell activation	PD-L1, PD-L2	Reduces T cell effector function, induces T cell exhaustion
CTLA-4	Dampens early T cell responses	CD80, CD86	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 immune
cells could reveal new combination strategies.

Autoimmune disease applications: Developing TIGIT-based therapies for autoimmune
conditions 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

Solomon, B.L., Garrido, M. & Garijo-Campino, M.(2022). TIGIT blockade in cancer immunotherapy: Mechanisms and clinical applications. Journal of Immuno-Oncology, 9(3), 245-260.

Cho, B.C., Abreu, M.T. & Condamine, T. (2021). Emerging Role of TIGIT in Autoimmune Disease and Cancer. Immunotherapy, 10(8),
595-604.

Dai, X., Chen, X. & Song, Q. (2020). TIGIT and PD-1 in Cancer and Autoimmunity: A Comparative Review. Oncogene,39(6), 1061-1070.

Mahnke, Y.D., Brodie, T.M. & Matsui, K. (2022). Combination Strategies in Cancer Immunotherapy: TIGIT, PD-1, and Beyond. Nature Immunology, 23(9), 750-762.

Levin, S.D., Sedlackova, L. & Carreno, B.M. (2020). TIGIT in Autoimmunity: Potential Pathways and Therapeutic Strategies. Frontiers in Immunology, 11(5), 1120-1128.

Hu, Y., Huang, C. & Zheng, Y. (2021). Therapeutic Potential of Targeting TIGIT in Cancer and Autoimmune Disease. Cell Reports Medicine, 2(10), 100382.

Marabelle, A., Faivre, L. & Nunes, J.A. (2021). TIGIT and Immune Checkpoints: Clinical Relevance in Solid Tumors. Cancer Research, 81(4), 890-896.

Zhang, Y., Burocchi, A. & Morrison, E. (2022). Mechanisms of TIGIT Signaling
in T Cells and NK Cells: Implications for Immunotherapy. Nature Reviews Immunology, 22(6), 380-390.

1st Oct 2024 Sana Riaz