TIGIT is a T cell immunoreceptor with both Ig and ITIM domains. It is an inhibitory receptor, also known as VSIG9 and VSTM3. It binds with high affinity to the poliovirus receptor (PVR), leading to increased IL-10 secretion and decreased IL-12B secretion. It also inhibits T cell activation by promoting the generation of mature immunoregulatory dendritic cells. TIGIT has been shown to be crucial in inducing immunosuppression in cancer immunotherapy.
Expression distribution of TIGIT
In humans, TIGIT is expressed by activated CD8+ T and CD4+ T cells, natural killer (NK) cells, regulatory T cells (Tregs), and follicular T helper cells.
(Data source: uniprot)
TIGIT is also overexpressed in many cancers, including breast cancer, lung adenocarcinoma, renal cell carcinoma, hepatocellular carcinoma, gastric cancer, blood tumors, etc.
Structure and ligands of TIGIT
TIGIT is a type I membrane protein. The TIGIT gene is located on chromosome 3q13.31 and encodes 244 amino acids. It has an extracellular immunoglobulin variable (IgV) domain, a type I transmembrane domain and a highly conserved intracellular inhibitory domain (containing ITIM and ITT motifs).
(Data source: uniprot)
The ligands of TIGIT are PVR, CD112, CD113, and PVRL4, with PVRL4 being the primary ligand due to the high-affinity interaction between TIGIT and PVR. TIGIT has much lower binding affinity for CD112 and CD113.
(Data source: Chiang EY, Mellman I. J Immunother Cancer. 2022)
TIGIT inhibition mechanism:
TIGIT's direct inhibitory mechanism is to directly inhibit the cytotoxic activity of T cells and NK cells by competitively antagonizing the stimulatory effect of CD226. CD226 is activated upon binding to CD155 or CD112, thereby activating LFA-1, changing the conformation of ICAM-1, recruiting Fyn, and driving the activation of the Akt signaling pathway, leading to the release of IFN-γ. Secondly, TIGIT can bind to CD155, where its ITT-like motif interacts with Grb2 and recruits SHIP1, thereby inhibiting the PI3K, MAPK, and NF-κB signaling pathways, leading to T cell and NK cell exhaustion and reduced interferon-γ production.
(Data source: Chu X, et al. Mol Cancer. 2023)
TIGIT exerts an indirect inhibitory effect by triggering CD155 to induce DCs to acquire an immature, tolerant phenotype, increase IL-10 secretion, and reduce IL-12 production. TIGIT can promote the differentiation of naive T cells into Treg cells more frequently and upregulate Foxp3 expression, thereby endowing Treg cells with better suppressive function. Finally, activation of the TIGIT/CD155 pathway can promote IL-10 transcription and induce macrophage polarization to transform into an anti-inflammatory M2 cytokine profile.
(Data source: Chu X, et al. Mol Cancer. 2023)
TIGIT targeted therapy and antibody drugs:
TIGIT monoclonal antibody blockade: Development of monoclonal antibodies targeting TIGIT, such as Tiragolumab and Vibostolimab, which bind to TIGIT, block the interaction between TIGIT and its ligand CD155, reduce immunosuppressive signals, and enhance the activity of T cells and NK cells.
TIGIT combined with checkpoint blockade: TIGIT is typically co-expressed with PD-1 on a variety of T cells. Furthermore, PD-1 blockade can increase TIGIT expression on CD8+ T cells. Co-expression of TIGIT and PD-1 manifests an immunosuppressive phenotype that exhausts T cells or Tregs. Dual blockade of TIGIT and PD-1 has the potential to be an effective anti-cancer therapy. By combining TIGIT with PD-1 inhibitors, all tumor-reactive CD8+ T cells are activated, enhancing the immune system's attack on tumors.
(Data source: Chiang EY, Mellman I. J Immunother Cancer. 2022)
Tiragolumab (Genentech) is an IgG1 anti- TIGIT drug developed by Roche. Currently, several clinical studies are underway, including SKYSCRAPER-01/03/05/15 for non-small cell lung cancer (NSCLC), SKYSCRAPER-07/08 for esophageal cancer (EC), SKYSCRAPER-09 for squamous cell head and neck cancer (SCCHN), SKYSCRAPER-11 for advanced solid tumors, and SKYSCRAPER-14 for hepatocellular carcinoma (HCC). However, in July of this year, Roche announced the termination of the Phase II/III study (SKYSCRAPER-06) of tiragolumab in metastatic non-squamous NSCLC.
Vibostolimab is an anti-TIGIT monoclonal antibody that inhibits the interaction between TIGIT and its ligand. Merck is combining it with the PD-1 monoclonal antibody pembrolizumab in clinical trials for multiple tumor indications.
Ociperlimab, a humanized anti-TIGIT IgG1 monoclonal antibody discovered by BeOne Medicines, is currently being evaluated in two global Phase 3 clinical trials: AdvanTIG-301 (NCT04866017) and AdvanTIG-302 (NCT04746924), both in combination with TEVIMBRA® for the treatment of non-small cell lung cancer (NSCLC). The ociperlimab development program has enrolled approximately 1,000 patients to date, including six global clinical trials in patients with lung cancer, esophageal squamous cell carcinoma, and cervical cancer.
(Data source: New Drug Intelligence Database)
