In 2024, the field of tumor immunotherapy has been dynamic, with multiple pharmaceutical giants continuing to invest heavily in the TIGIT (T cell immunoreceptor with immunoglobulin and ITIM domains) target. Although some Phase III studies have encountered setbacks, recent positive data from the combination of Tiragolumab (anti-TIGIT monoclonal antibody) with Atezolizumab (anti-PD-L1) in the treatment of PD-L1 high-expressing non-small cell lung cancer have reignited industry hopes for TIGIT as a next-generation immune checkpoint inhibitor.
 

The TIGIT target has emerged as a star in tumor immunotherapy due to its unique immune regulatory mechanisms. Let's explore it in depth!

 

Introduction to the TIGIT Target
 

TIGIT is an immune checkpoint protein primarily expressed on the surface of T cells and NK cells (natural killer cells). It belongs to the immunoglobulin superfamily, with a structure that includes an extracellular immunoglobulin variable (IgV) domain, a transmembrane region, and an intracellular cytoplasmic tail containing an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoglobulin tyrosine tail (ITT). This structure enables TIGIT to transmit inhibitory signals and play a key role in suppressing immune responses. Through high-affinity binding with ligands such as CD155 (PVR), TIGIT plays a critical immune checkpoint role in the tumor microenvironment.
 

 

(Image placeholder: TIGIT in cancer immunotherapy)
 

I.  Tumor Immune Escape: Three Major Inhibitory Mechanisms of TIGIT
 

TIGIT suppresses immune cell activity and promotes tumor immune escape through multiple mechanisms, primarily including the following three aspects:First, on dendritic cells (DCs), TIGIT binding to CD155 induces inhibitory signals from CD155, thereby inhibiting DC maturation and activation, weakening their antigen presentation function, and ultimately preventing effective T cell activation.Second, on T cells and NK cells, TIGIT binding to CD155 recruits and activates phosphatases such as SHP1/2 through its intracellular ITIM and ITT domains, leading to dephosphorylation and inhibition of key signaling molecules like CD3ζ and ZAP70, directly suppressing T cell and NK cell activation and cytotoxic functions.Additionally, TIGIT competitively binds to CD155 with the co-stimulatory receptor CD226. Due to TIGIT's higher affinity for CD155, it effectively "occupies" the ligand, thereby blocking CD226-mediated activation signals in T cells and NK cells.
 

 

(Image placeholder: TIGIT in cancer immunotherapy)
 

II.  Autoimmune Diseases: The Complex Regulatory Role of TIGIT
 

A) Rheumatoid ArthritisIn rheumatoid arthritis (RA), decreased TIGIT expression in CD4⁺ T cells negatively correlates with disease activity, and TIGIT overexpression can inhibit the production of pro-inflammatory cytokines IFN-γ and IL-17 while increasing anti-inflammatory cytokine IL-10, thereby alleviating arthritis in models. However, on follicular helper T cells (Tfh), TIGIT may promote their survival by upregulating anti-apoptotic molecules (such as Bcl-xL), thereby enhancing B cell activation and autoantibody production. Furthermore, on natural killer (NK) cells, TIGIT acts as a negative regulator, and its expression is significantly reduced in RA patients, potentially leading to excessive NK cell activation and exacerbating inflammation.
 

B) Systemic Lupus Erythematosus
 

In systemic lupus erythematosus (SLE), increased TIGIT expression in CD4⁺ T cells positively correlates with disease activity, and through binding to CD155, it negatively regulates CD4⁺ T cell proliferation and IFN-γ production, playing a protective role. However, in follicular helper T cells (Tfh), TIGIT enhances their ability to help B cells, while follicular regulatory T cells (Tfr) with high TIGIT expression can inhibit autoantibody production, demonstrating its cell subset-specific functions. On NK cells, TIGIT expression is significantly reduced in SLE patients, and blocking the TIGIT pathway can restore NK cell function, indicating that TIGIT exerts continuous negative regulation on NK cells.
 

C) Inflammatory Bowel Disease
 

In inflammatory bowel disease (IBD), TIGIT expression on CD4⁺ and CD8⁺ T cells in the mucosa is significantly reduced during active disease. Regarding regulatory T cells (Treg), TIGIT serves as a marker of activated Tregs and can enhance their immunosuppressive function; in chronic colitis models, enhancing TIGIT signaling can alleviate inflammation. Notably, CD155 on dendritic cells (DCs) binding to TIGIT on Treg surfaces reduces the production of pro-inflammatory cytokine IL-12. On NK cells, TIGIT expression is elevated in IBD patients, and blocking TIGIT can enhance NK cell function.

 

Mouse Models
 

● TIGIT KO Mice: Used to study the fundamental effects of TIGIT gene deletion on immune system function and anti-tumor immune responses.
 

● TIGIT Humanized Mice: Replace the mouse Tigit gene with the human TIGIT gene, used to evaluate the in vivo efficacy and safety of antibodies targeting human TIGIT.
 

● hTIGIT/hPD-L1 Double Humanized Mice: Simultaneously express human TIGIT and human PD-L1, specifically designed for precise evaluation of combination therapy with TIGIT and PD-1/PD-L1 inhibitors.
 

MingCeler Biotech Facilitates Mechanism Research and Drug Development
 

Gene therapy offers hope for common diseases, but its development and validation are inseparable from animal model support. Leveraging its self-developed TurboMice™ technology, MingCeler Biotech has established multiple disease mouse models. The TurboMice™ technology overcomes the challenges of long modeling cycles and low success rates for complex models. It enables editing at virtually any target genomic locus and can generate complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as two months.
 

MingCeler Biotech can customize various TIGIT-related mouse models according to client needs, such as TIGIT KO mice, TIGIT humanized mice, and hTIGIT/hPD-L1 double humanized mice. We welcome inquiries!
 

References:

[1] Chauvin J, Zarour HM. TIGIT in cancer immunotherapy. Journal for ImmunoTherapy of Cancer. 2020;8:e000957. https://doi.org/10.1136/jitc-2020-000957

[2] Yue C, Gao S, Li S, Xing Z, Qian H, Hu Y, Wang W, Hua C. TIGIT as a Promising Therapeutic Target in Autoimmune Diseases. Front Immunol. 2022 Jun 3;13:911919. doi: 10.3389/fimmu.2022.911919. PMID: 35720417; PMCID: PMC9203892.

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