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Cellular and Molecular Biology

TIGIT antibody with PVR competitive ability enhances cancer immunotherapy and capable of eliciting anti-tumour immune memory

British Journal of Cancer volume 133, pages 743–755 (2025)Cite this article

Subjects

A Correction to this article was published on 12 August 2025

This article has been updated

Abstract

Background

T-cell immunoreceptor with immunoglobulin (Ig) and ITIM domains (TIGIT) is a checkpoint receptor thought to be involved in mediating T-cell exhaustion and dysfunction of natural killer (NK) cells in tumours and is emerging as novel promising targets in immunotherapy, however, the ligand binding and the efficacy of its antibody still need to be further explored.

Methods

Four different TIGIT antibodies in characteristics of antigen binding, in vitro effects on activated T cells, Fc region functions and tumour inhibition in animal models were compared. The antibody as monotherapy and combined with anti-PD-L1 antibody, effects on PBMC in ex vivo coculture with autologous human CRC organoids as well as PK profile were evaluated.

Results

Studies demonstrated that TIGIT antibody with PVR-competitive ability as monotherapy resulted in inhibition of tumour growth, sustained anti-tumour immune memory in tumour re-challenge mice, enhanced anti-tumour therapy in combination with anti-PD-L1. Ex vivo coculture assay suggested that TIGIT antibody treatment activated immune cells and promoted infiltration and tumour killing ability of autologous PBMC in human CRC organoids.

Conclusions

Our study broadens the knowledge of TIGIT antibody in cancer immunotherapy and may benefit future development of next-generation checkpoint inhibitors with improved clinical outcomes.

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Fig. 1: Binding affinity and competitive activity of TIGIT antibodies.
Fig. 2: The binding epitope comparison of TIGIT antibodies.
Fig. 3: T-cell activation ability of different TIGIT antibodies.
Fig. 4: In vivo efficacy of different TIGIT antibodies as monotherapy.
Fig. 5: Combination treatment of TIGIT antibody with atezolizumab in CT26 bearing B-huTIGIT transgene mice.
Fig. 6: TIGIT antibodies promoted infiltration and tumour killing activities of autologous PBMC in ex vivo human CRC organoids.

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Data availability

All data analysed during this study are included in this published article.

Change history

  • 07 August 2025

    The original online version of this article was revised: In this article the author contribution statement was originally missing; this has now been corrected. The author contribution statement is as follows: These authors contributed equally: Huijuan Yu, Shaowen Jin.

  • 12 August 2025

    A Correction to this paper has been published: https://doi.org/10.1038/s41416-025-03084-4

References

  1. Worboys JD, Vowell KN, Hare RK, Ambrose AR, Bertuzzi M, Conner MA, et al. TIGIT can inhibit T cell activation via ligation-induced nanoclusters, independent of CD226 co-stimulation. Nat Commun. 2023;14:5016 https://doi.org/10.1038/s41467-023-40755-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Liu S, Zhang H, Li M, Hu D, Li C, Ge B, et al. Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells. Cell Death Differ. 2013;20:456–64. https://doi.org/10.1038/cdd.2012.141.

    Article  CAS  PubMed  Google Scholar 

  3. Khan M, Arooj S, Wang H. NK cell-based immune checkpoint inhibition. Front Immunol. 2020;11:167 https://doi.org/10.3389/fimmu.2020.00167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Valhondo I, Hassouneh F, Lopez-Sejas N, Pera A, Sanchez-Correa B, Guerrero B, et al. Characterization of the DNAM-1, TIGIT and TACTILE axis on circulating NK, NKT-Like and T cell subsets in patients with acute myeloid leukemia. Cancers. 2020;12:2171–89. https://doi.org/10.3390/cancers12082171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cho BC, Abreu DR, Hussein M, Cobo M, Patel AJ, Secen N, et al. Tiragolumab plus atezolizumab versus placebo plus atezolizumab as a first-line treatment for PD-L1-selected non-small-cell lung cancer (CITYSCAPE): primary and follow-up analyses of a randomised, double-blind, phase 2 study. Lancet Oncol. 2022;23:781–92. https://doi.org/10.1016/S1470-2045(22)00226-1.

    Article  CAS  PubMed  Google Scholar 

  6. Finn RS, Hsu CH, Li D, Burgoyne A, Cotter C, et al. Results from the MORPHEUS-liver study: phase Ib/II randomized evaluation of tiragolumab (tira) in combination with atezolizumab (atezo) and bevacizumab (bev) in patients with unresectable, locally advanced or metastatic hepatocellular carcinoma (uHCC). J Clin Oncol. 2023;41:1.

    Article  Google Scholar 

  7. Roche reports update on Phase III SKYSCRAPER-01 study results. News release Roche. 2024. https://www.roche.com/media/releases/med-cor-2024-11-26.

  8. Rudin CM, Liu SV, Soo RA, Lu S, Hong MH, Lee JS, et al. SKYSCRAPER-02: tiragolumab in combination with atezolizumab plus chemotherapy in untreated extensive-stage small-cell lung cancer. J Clin Oncol. 2024;42:324–35. https://doi.org/10.1200/JCO.23.01363.

    Article  CAS  PubMed  Google Scholar 

  9. Socinski MA, Rodriguez Abreu D, Lee DH, Cappuzzo F, Nishio M, Lovly CM, et al. LBA2 SKYSCRAPER-06: efficacy and safety of tiragolumab plus atezolizumab plus chemotherapy (tira + atezo + chemo) vs pembrolizumab plus chemotherapy (pembro + chemo) in patients (pts) with advanced non-squamous non-small cell lung cancer (NSq NSCLC). Immuno-Oncol. Technol. 2024;24; https://doi.org/10.1016/j.iotech.2024.101025.

  10. Rudin CM, Liu SV, Soo RA, Lu S, Hong MH, Lee JS, et al. KeyVibe-008: randomized, phase 3 study of first-line vibostolimab plus pembrolizumab plus etoposide/platinum versus atezolizumab plus EP in extensive-stage small cell lung cancer. J Clin Oncol. 2024;42:324–35. https://doi.org/10.1200/JCO.23.01363.

    Article  CAS  PubMed  Google Scholar 

  11. GlobeNewswire. iTeos Therapeutics Announces Late-Breaking Oral Presentation of Phase 2 GALAXIES Lung-201 Interim Data at the European Society for Medical Oncology Congress 2024. iTeos Therapeutics Inc. 2024.

  12. Janjigian YY, Oh DY, Pelster MS, Wainberg ZA, Sison EA, Jack R, et al. EDGE-gastric arm A1- phase 2 study of domvanalimab, zimberelimab, and FOLFOX in first-line (1L) advanced gastroesophageal cancer. J Clin Oncol. 2023;41:1.

    Article  Google Scholar 

  13. Johnson ML, Fox W, Lee YG, Lee KH, Ahn HK, Kim YC, et al. ARC-7- randomized phase 2 study of domvanalimab + zimberelimab ± etrumadenant versus zimberelimab in first-line, metastatic, PD-L1-high non-small cell lung cancer (NSCLC). J Clin Oncol. 2022;40:1.

  14. Naidoo J, Peters S, Runglodvatana Y, Li JY-C, Fong CH, Ho GF, et al. Phase 2 randomized study of domvanalimab combined with zimberelimab in front-line, PD-(L)1 high, locally advanced or metastatic non-small cell lung cancer (NSCLC): results from ARC-10 part 1. J Immunother Cancer. 2024;12(Suppl 3):A1690–A1691. https://doi.org/10.1136/jitc-2024-SITC2024.1461.

  15. Zhang Q, Bi J, Zheng X, Chen Y, Wang H, Wu W, et al. Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nat Immunol. 2018;19:723–32. https://doi.org/10.1038/s41590-018-0132-0.

    Article  CAS  PubMed  Google Scholar 

  16. Xu F, Sunderland A, Zhou Y, Schulick RD, Edil BH, Zhu Y. Blockade of CD112R and TIGIT signaling sensitizes human natural killer cell functions. Cancer Immunol Immunother. 2017;66:1367–75. https://doi.org/10.1007/s00262-017-2031-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Boles KS, Vermi W, Facchetti F, Fuchs A, Wilson TJ, Diacovo TG, et al. A novel molecular interaction for the adhesion of follicular CD4 T cells to follicular DC. Eur J Immunol. 2009;39:695–703. https://doi.org/10.1002/eji.200839116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yu X, Harden K, Gonzalez LC, Francesco M, Chiang E, Irving B, et al. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol. 2009;10:48–57. https://doi.org/10.1038/ni.1674.

    Article  CAS  PubMed  Google Scholar 

  19. Brauneck F, Fischer B, Witt M, Muschhammer J, Oelrich J, da Costa Avelar PH, et al. TIGIT blockade repolarizes AML-associated TIGIT(+) M2 macrophages to an M1 phenotype and increases CD47-mediated phagocytosis. J Immunother Cancer. 2022;10:e004794. https://doi.org/10.1136/jitc-2022-004794.

  20. Shin SM, Choi DK, Jung K, Bae J, Kim JS, Park SW, et al. Antibody targeting intracellular oncogenic Ras mutants exerts anti-tumour effects after systemic administration. Nat Commun. 2017;8:15090 https://doi.org/10.1038/ncomms15090.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Sanchez-Correa B, Valhondo I, Hassouneh F, Lopez-Sejas N, Pera A, Bergua JM, et al. DNAM-1 and the TIGIT/PVRIG/TACTILE axis: novel immune checkpoints for natural killer cell-based cancer immunotherapy. Cancers. 2019;11:877 https://doi.org/10.3390/cancers11060877.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lu Y, Huang Y, Huang L, Xu Y, Wang Z, Li H, et al. CD16 expression on neutrophils predicts treatment efficacy of capecitabine in colorectal cancer patients. BMC Immunol. 2020;21:46–60. https://doi.org/10.1186/s12865-020-00375-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang XY, Wang B, Wen YM. From therapeutic antibodies to immune complex vaccines. NPJ Vaccines. 2019;4:2 https://doi.org/10.1038/s41541-018-0095-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Liu H, Guo L, Zhang J, Zhou Y, Zhou J, Yao J, et al. Glycosylation-independent binding of monoclonal antibody toripalimab to FG loop of PD-1 for tumor immune checkpoint therapy. MAbs. 2019;11:681–90. https://doi.org/10.1080/19420862.2019.1596513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Oostindie SC, Lazar GA, Schuurman J, Parren P. Avidity in antibody effector functions and biotherapeutic drug design. Nat Rev Drug Discov. 2022;21:715–35. https://doi.org/10.1038/s41573-022-00501-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhang B, Zhang J, Li Y, Li N, Wang Y, Jang R, et al. In situ STING-activating nanovaccination with TIGIT blockade for enhanced immunotherapy of anti-PD-1-resistant tumors. Adv Mater. 2023;35:e2300171 https://doi.org/10.1002/adma.202300171.

    Article  CAS  PubMed  Google Scholar 

  27. Guan X, Hu R, Choi Y, Srivats S, Nabet BY, Silva J, et al. Anti-TIGIT antibody improves PD-L1 blockade through myeloid and T(reg) cells. Nature. 2024;627:646–55. https://doi.org/10.1038/s41586-024-07121-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kim TW, Bedard PL, LoRusso P, Gordon MS, Bendell J, Oh DY, et al. Anti-TIGIT antibody tiragolumab alone or with atezolizumab in patients with advanced solid tumors: a phase 1a/1b nonrandomized controlled trial. JAMA Oncol. 2023;9:1574–82. https://doi.org/10.1001/jamaoncol.2023.3867.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Dekkers G, Bentlage AEH, Stegmann TC, Howie HL, Lissenberg-Thunnissen S, Zimring J, et al. Affinity of human IgG subclasses to mouse Fc gamma receptors. MAbs. 2017;9:767–73. https://doi.org/10.1080/19420862.2017.1323159.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Dimitrov DS. Therapeutic proteins. Methods Mol Biol. 2012;899:1–26. https://doi.org/10.1007/978-1-61779-921-1_1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Liu L. Pharmacokinetics of monoclonal antibodies and Fc-fusion proteins. Protein Cell. 2018;9:15–32. https://doi.org/10.1007/s13238-017-0408-4.

    Article  CAS  PubMed  Google Scholar 

  32. Suzuki T, Ishii-Watabe A, Tada M, Kobayashi T, Kanayasu-Toyoda T, Kawanishi T, et al. Importance of neonatal FcR in regulating the serum half-life of therapeutic proteins containing the Fc domain of human IgG1: a comparative study of the affinity of monoclonal antibodies and Fc-fusion proteins to human neonatal FcR. J Immunol. 2010;184:1968–76. https://doi.org/10.4049/jimmunol.0903296.

    Article  CAS  PubMed  Google Scholar 

  33. Joller N, Lozano E, Burkett PR, Patel B, Xiao S, Zhu C, et al. Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity. 2014;40:569–81. https://doi.org/10.1016/j.immuni.2014.02.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Levin SD, Taft DW, Brandt CS, Bucher C, Howard ED, Chadwick EM, et al. Vstm3 is a member of the CD28 family and an important modulator of T-cell function. Eur J Immunol. 2011;41:902–15. https://doi.org/10.1002/eji.201041136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Judge SJ, Darrow MA, Thorpe SW, Gingrich AA, O’Donnell EF, Bellini AR, et al. Analysis of tumor-infiltrating NK and T cells highlights IL-15 stimulation and TIGIT blockade as a combination immunotherapy strategy for soft tissue sarcomas. J Immunother Cancer. 2020;8:e001355. https://doi.org/10.1136/jitc-2020-001355.

  36. Guillerey C, Harjunpaa H, Carrie N, Kassem S, Teo T, Miles K, et al. TIGIT immune checkpoint blockade restores CD8(+) T-cell immunity against multiple myeloma. Blood. 2018;132:1689–94. https://doi.org/10.1182/blood-2018-01-825265.

    Article  CAS  PubMed  Google Scholar 

  37. Kong Y, Zhu L, Schell TD, Zhang J, Claxton DF, Ehmann WC, et al. T-cell immunoglobulin and ITIM domain (TIGIT) associates with CD8+ T-cell exhaustion and poor clinical outcome in AML patients. Clin Cancer Res. 2016;22:3057–66. https://doi.org/10.1158/1078-0432.CCR-15-2626.

    Article  CAS  PubMed  Google Scholar 

  38. Chauvin JM, Zarour HM. TIGIT in cancer immunotherapy. J Immunother Cancer. 2020;8:e000957. https://doi.org/10.1136/jitc-2020-000957.

  39. Schorer M, Rakebrandt N, Lambert K, Hunziker A, Pallmer K, Oxenius A, et al. TIGIT limits immune pathology during viral infections. Nat Commun. 2020;11:1288 https://doi.org/10.1038/s41467-020-15025-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Fourcade J, Sun Z, Chauvin JM, Ka M, Davar D, Pagliano O, et al. CD226 opposes TIGIT to disrupt Tregs in melanoma. JCI Insight. 2018;3:e121157. https://doi.org/10.1172/jci.insight.121157.

  41. Kurtulus S, Sakuishi K, Ngiow SF, Joller N, Tan DJ, Teng MW, et al. TIGIT predominantly regulates the immune response via regulatory T cells. J Clin Investig. 2015;125:4053–62. https://doi.org/10.1172/JCI81187.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Tekguc M, Wing JB, Osaki M, Long J, Sakaguchi S. Treg-expressed CTLA-4 depletes CD80/CD86 by trogocytosis, releasing free PD-L1 on antigen-presenting cells. Proc Natl Acad Sci USA. 2021;118:e2023739118. https://doi.org/10.1073/pnas.2023739118.

  43. Walker LS. Treg and CTLA-4: two intertwining pathways to immune tolerance. J Autoimmun. 2013;45:49–57. https://doi.org/10.1016/j.jaut.2013.06.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Han JH, Cai M, Grein J, Perera S, Wang H, Bigler M, et al. Effective anti-tumor response by TIGIT blockade associated with FcγR engagement and myeloid cell activation. Front Immunol. 2020;11:573405 https://doi.org/10.3389/fimmu.2020.573405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Waight JD, Chand D, Dietrich S, Gombos R, Horn T, Gonzalez AM, et al. Selective FcgammaR Co-engagement on APCs modulates the activity of therapeutic antibodies targeting T cell antigens. Cancer Cell. 2018;33:1033–1047.e1035. https://doi.org/10.1016/j.ccell.2018.05.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Geels SN, Moshensky A, Sousa RS, Murat C, Bustos MA, Walker BL, et al. Interruption of the intratumor CD8(+) T cell:Treg crosstalk improves the efficacy of PD-1 immunotherapy. Cancer Cell. 2024;42:1051–1066.e1057. https://doi.org/10.1016/j.ccell.2024.05.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Banta KL, Xu X, Chitre AS, Au-Yeung A, Takahashi C, O’Gorman WE, et al. Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates co-blockade to optimize anti-tumor CD8(+) T cell responses. Immunity. 2022;55:512–526 e519. https://doi.org/10.1016/j.immuni.2022.02.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant No. 82104228), the GDAS Special Project of Science and Technology Development (Grant No. 2021GDASYL–20210103057, 2023GDASZH-2023030602-01).

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Author notes

  1. These authors contributed equally: Huijuan Yu, Shaowen Jin.

Authors and Affiliations

  1. Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China

    Huijuan Yu & Xiaofei Wang

  2. Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

    Shaowen Jin

  3. Guangdong Annpobio Co., Ltd, Guangzhou, China

    Min Zeng, Zhiqing Yang & Xiaofei Wang

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  1. Huijuan Yu
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  3. Min Zeng
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Contributions

Xiaofei Wang contributed to the conception and design of the study, Huijuan Yu, Min Zeng, Zhiqing Yang and Shaowen Jin were involved in data collection, analysis, and interpretation. Huijuan Yu contributed to drafting the manuscript. Xiaofei Wang provided critical revisions. All authors approved the final version of the manuscript and agreed to be accountable for all aspects of the work.

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Correspondence to Xiaofei Wang.

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The original online version of this article was revised: In this article the author contribution statement was originally missing; this has now been corrected. The author contribution statement is as follows: These authors contributed equally: Huijuan Yu, Shaowen Jin.

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Yu, H., Jin, S., Zeng, M. et al. TIGIT antibody with PVR competitive ability enhances cancer immunotherapy and capable of eliciting anti-tumour immune memory. Br J Cancer 133, 743–755 (2025). https://doi.org/10.1038/s41416-025-03046-w

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