TIGIT

  • T-cell immunoreceptor with Ig and ITIM domains (TIGIT)
  • Gene Location: chromosome 3q13.33

Biology

  • TIGIT is encoded by the TIGIT gene, located on chromosome 3q13.33. It functions as an inhibitory immune checkpoint receptor and is prominently expressed on exhausted CD8⁺ T cells, regulatory T cells (Tregs), and natural killer (NK) cells within the tumor microenvironment.1
  • TIGIT binds to CD155 (PVR) expressed on tumor and antigen-presenting cells, resulting in downregulation of T-cell activation, cytokine production, and NK cell cytotoxicity—thereby promoting immune escape and tumor progression.1

Etiology and Epidemiology

  • TIGIT expression is significantly elevated in gastric adenocarcinoma compared with normal gastric mucosa, with increased expression observed on tumor-infiltrating lymphocytes and peripheral CD8⁺ T cells from gastric cancer patients.2
  • In a pooled analysis of immunohistochemistry (IHC) studies, 77.8% of gastric cancer cases showed high TIGIT expression in tumor cells (defined as > 5% of cells staining positive).3
  • Co-expression with PD-1 is common in tumor-infiltrating lymphocytes, particularly in patients with high-grade, microsatellite-stable tumors.4
  • In gastric cancer, TIGIT upregulation correlates with poor prognosis and a suppressive immune landscape.1-2
  • TIGIT expression increases with cancer stage and is associated with lymph node metastasis.5
  • Dual inhibition of TIGIT and PD-1/PD-L1 has shown synergistic potential in preclinical models by restoring T-cell function and enhancing antitumor immunity. TIGIT is therefore an emerging immunotherapeutic target, and combination strategies are actively being explored in early-phase clinical trials in gastric and other solid tumors.6

Testing

When to Test:

  • While TIGIT testing is not yet part of standard clinical biomarker panels, its relevance is growing in the context of advanced or metastatic gastric cancer, particularly for patients being evaluated for immune checkpoint inhibitor therapy or enrollment in early-phase clinical trials.²

Available Testing Methods:

  • IHC is the most commonly used method for TIGIT detection in tumor-infiltrating lymphocytes.1
  • Multiplex immunofluorescence (mIF), primarily used in translational research settings, allows for simultaneous detection of TIGIT alongside multiple immune markers, providing insights into the functional immune context and cell–cell interactions.¹
  • Flow cytometry is often applied in research and clinical trials for functional profiling of TIGIT⁺ immune cell subsets, including circulating and tumor-infiltrating T cells and NK cells. Flow cytometry enables evaluation of co-expression patterns, immune exhaustion markers, and cytokine profiles.1

Testing Guideline Recommendations:

  • Although TIGIT is not currently part of standard biomarker testing panels, it remains an active focus of investigation in combination immunotherapy trials, with ongoing studies expected to inform its potential integration into future clinical practice.7
  • NCCN Gastric Cancer Guidelines (v7.2025) recommend that patients with progressive disease after standard therapies should be considered for clinical trials of novel immune checkpoints, including antiTIGIT agents.7

Targeted Therapy

Approved Agents:

  • There are no FDA-approved TIGIT-targeted agents as of 2025.

Investigational Agents:

  • Domvanalimab8
    • Domvanalimab is a humanized, Fc-silent IgG1 monoclonal antibody that targets TIGIT, an inhibitory immune checkpoint receptor expressed on CD8⁺ T cells, Tregs, and NK cells.
    • Domvanalimab is being developed as part of combination immunotherapy strategies in multiple solid tumors, including non–small cell lung cancer and gastroesophageal adenocarcinoma.
  • Mechanism of Action8
    • Domvanalimab selectively binds to TIGIT and prevents its interaction with CD155 (PVR), a ligand expressed on tumor and antigen-presenting cells.
    • This blockade relieves TIGIT-mediated suppression of effector immune responses, thereby enhancing T-cell activation, cytokine production, and NK cell cytotoxicity.
    • Importantly, its Fc-silent design reduces the potential for antibody-dependent cellular cytotoxicity (ADCC), preserving regulatory immune cell populations and potentially improving tolerability.

Investigational Studies:

  • ARC-21 (EDGE-Gastric) Study
    • ClinicalTrials.gov: NCT05329766
    • Study design:
      • A phase 1b/2 trial evaluating domvanalimab + zimberelimab + chemotherapy in first-line upper GI cancers, including gastric adenocarcinoma.9
    • Key outcomes:
      • Domvanalimab (anti-TIGIT) + zimberelimab (anti–PD-1) with chemotherapy showed over 12 months median progression-free survival in first-line upper GI cancers (gastric, GEJ, esophageal) in the phase II ARC-21 trial.8
      • The combination was well tolerated, with durable disease control and early signs of synergy in PD-L1–positive patients.5
  • STAR-221 Study
    • ClinicalTrials.gov: NCT05568095
    • Study design:
      • Randomized, open-label, multicenter phase 3 trial of domvanalimab + zimberelimab + chemotherapy versus nivolumab + chemotherapy in participants with previously untreated, locally advanced, unresectable or metastatic gastric, gastroesophageal junction, and esophageal adenocarcinoma.10

References

  1. Zhang P, Liu X, Gu Z, et al. Targeting TIGIT for cancer immunotherapy: recent advances and future directions. Biomark Res. 2024;12(1):7. doi:10.1186/s40364-023-00543-z
  2. He W, Zhang H, Han F, et al. CD155T/TIGIT signaling regulates CD8+ T-cell metabolism and promotes tumor progression in human gastric cancer. Cancer Res. 2017;77(22):6375-6388. doi:10.1158/0008-5472.CAN-17-0381
  3. Xiao K, Xiao K, Li K, Xue P, Zhu S. Prognostic role of TIGIT expression in patients with solid tumors: a meta-analysis. J Immunol Res. 2021;2021:5440572. doi:10.1155/2021/5440572.
  4. Zeng Z, Zhu Q. Progress and prospects of biomarker-based targeted therapy and immune checkpoint inhibitors in advanced gastric cancer. Front Oncol. 2024;14. doi:https://doi.org/10.3389/fonc.2024.1382183
  5. Wainberg ZA. Dr Wainberg on phase 2 domvanalimab/zimberelimab/chemo data in gastric cancer. OncLive. 2025;1. https://www.onclive.com/view/dr-wainberg-on-phase-2-domvanalimab-zimberelimab-chemo-data-in-gastric-cancer
  6. Xu D, Zhao E, Zhu C, et al. TIGIT and PD-1 may serve as potential prognostic biomarkers for gastric cancer. Immunobiology. 2020;225(3):151915. doi:10.1016/j.imbio.2020.151915
  7. ‌‌National Comprehensive Cancer Network. Clinical practice guidelines in oncology: gastric cancer. Version 2.2025. https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf
  8. Anti-TIGIT – Domvanalimab. Arcus Biosciences, Inc, 2025. https://arcusbio.com/our-science/clinical-candidates/domvanalimab/?utm_source=chatgpt.com
  9. A safety and efficacy study of treatment combinations with and without chemotherapy in adult participants with advanced upper gastrointestinal tract malignancies (EDGE-Gastric). ClinicalTrials.gov. Updated June 27, 2025. Accessed July 10, 2025. https://www.clinicaltrials.gov/study/NCT05329766
  10. A clinical trial of a new combination treatment, domvanalimab and zimberelimab, plus chemotherapy, for people with an upper gastrointestinal tract cancer that cannot be removed with surgery that has spread to other parts of the body (STAR-221). ClinicalTrials.gov. Updated June 26, 2025. Accessed July 14, 2025. https://clinicaltrials.gov/study/NCT05568095