Explore TIGIT

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  • Pathway Overview
  • Role In Cancer
  • Targeting TIGIT
  • Potential of Combinations
Pathway Overview

TIGIT is an inhibitory receptor that plays a role in regulating T-cell–driven immune responses

T-cell immunoglobin and immunoreceptor tyrosine-based inhibitory motif (TIGIT) is expressed on lymphocytes, including activated T cells, regulatory T cells (Tregs), memory T cells, and natural killer (NK) cells.1,2

TIGIT primarily binds to its ligand, the poliovirus receptor (PVR), also called CD155.

  • PVR is highly expressed on dendritic cells (DCs), fibroblasts, endothelial cells, and some tumour cells1-3

TIGIT inhibits lymphocytes while its coreceptor CD226 activates lymphocytes

TIGIT and a coreceptor, CD226, both bind to PVR to maintain immune balance via opposing effects on lymphocytes.1

CD226 is an activating receptor that enhances
NK-cell and T-cell activity1

TIGIT and CD226

 

TIGIT "turns off" the immune response by
inhibiting NK-cell and T-cell activity4-7

TIGIT
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Role In Cancer

Tumours may employ aberrant TIGIT expression as a means of immune escape

TIGIT is expressed on tumour-infiltrating lymphocytes in multiple solid tumour types, including melanoma, colon, breast, lung, and renal cancer.2,3,8,9

  • Mouse models demonstrate that TIGIT expression is relatively low in the peripheral lymphoid organs but highly enriched in tumour tissue, indicating TIGIT regulates immune responses directly within the tumour microenvironment

TIGIT plays a key role in suppressing the antitumour immune response within the tumour microenvironment, via multiple direct and indirect mechanisms.3

Inactive T cell
Inactive NK cell
Tumour cell
TIGIT
CD226
PVR
CD226
PVR
TIGIT
 
 
 
 
TIGIT directly inhibits T cells and NK cells by competing with CD226 binding1,2

TIGIT and CD226 directly compete for ligand binding with PVR. However, preclinical research has shown that TIGIT has 100-fold higher binding affinity for PVR compared with CD226.1,2,11

  • When both TIGIT and CD226 are coexpressed, TIGIT effectively blocks the interaction of CD226 with PVR or disrupts CD226 homodimerisation

When expressed in the tumour microenvironment, TIGIT can therefore stop T cells and NK cells from killing tumour cells.2

  • TIGIT can directly inhibit CD8+ T cell effector function, suppressing T-cell activation and proliferation2,6,7,9,10  
  • TIGIT can inhibit NK cell effector function, preventing initial tumour cell death and release of cancer cell antigens2,4
TIGIT further inhibits the antitumour immune response via other mechanisms1,2
  • TIGIT may induce immunosuppressive dendritic cells
    • TIGIT on T cells can suppress dendritic cell costimulatory abilities, leading to reduced cancer antigen presentation and increased anti-inflammatory cytokines such as IL-101,2
  • TIGIT can affect T-cell priming and differentiation
    • Tregs expressing TIGIT or PVR-stimulated myeloid cells can suppress CD8+ T-cell effector function or skew CD4+ T cell polarisation2
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Targeting TIGIT

Blocking TIGIT-mediated T cell inhibition may help reinitiate the antitumour immune response

Inhibition of the TIGIT pathway may block immunosuppressive signalling, and also allow the CD226 pathway to resume its T-cell activating functions.2,9,11

  • TIGIT deficiency in mice significantly delayed the growth of both melanoma and colon carcinoma, and led to increased proliferation of CD8+ tumour-infiltrating lymphocytes
Active T cell
Active NK cell
Tumour cell
TIGIT
CD226
PVR
CD226
PVR
TIGIT
 
 
 
 
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Potential of Combinations

Targeting TIGIT together with PD-L1 may have a synergistic effect on restoring cancer immunity

Because tumours employ multiple mechanisms to evade the immune response, an approach involving a combination of immunotherapy targets to re-establish proper antitumour T-cell activity may provide therapeutic benefit.12,13

Combining inhibition of the TIGIT and PD-L1 pathways may have a synergistic effect on invigorating T-cell activity against tumour cells.2,8,11  

  • Preclinical data suggest that dual blockade of both the TIGIT and PD-L1 pathways may reverse T-cell exhaustion and improve cytotoxic T-cell effector function
  • Although blockade of either TIGIT or PD-L1 alone was sufficient to enhance cytotoxic T-cell effector function, blockade of both receptors was necessary to restore the potency of cytotoxic T cells within highly suppressive tumour microenvironments
 
 
 
 

Roche is actively investigating TIGIT as a novel cancer immunotherapy target, in combination with PD-L1 inhibition, across solid tumours

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References 
  1. Yu X, Harden K, Gonzalez LC. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol. 2009;10:48-57. PMID: 19011627
  2. Manieri NA, Chiang EY, Grogan JL. TIGIT: a key inhibitor of the cancer immunity cycle. Trends Immunol. 2017;38:20-28. PMID: 27793572
  3. Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity. 2016;44:989-1004. PMID: 27192565
  4. Stanietsky N, Simic Hrvoje, Arapovic J, et al. The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. Proc Natl Acad Sci. 2009;106:17858-17863. PMID: 19815499
  5. Liu S, Zhang H, Li M, 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;20:456-464. PMID: 23154388
  6. Joller N, Lozano E, Burkett PR, et al. Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity. 2014;40:569-581. PMID: 24745333
  7. Joller N, Hafler JP, Brynedal B, et al. Cutting edge: TIGIT has T cell-intrinsic inhibitory functions. J Immunol. 2011;186:1338-4132. PMID: 21199897
  8. Chauvin JM, Ornella P, Fourcade J, et al. TIGIT and PD-1 impair tumor antigen-specific CD8+ T cells in melanoma patients. J Clin Invest. 2015;125:2046-2058. PMID: 25866972
  9. Kurtulus S, Sakuishi K, Ngiow SF, et al. TIGIT predominantly regulates the immune response via regulatory T cells. J Clin Invest. 2015;125:4053-4062. PMID: 26413872
  10. Levin SD, Taft DW, Brandt CS, et al. Vstm3 is a member of the CD28 family and an important modulator of T-cell function. Eur J Immunol. 2011;41:902-915. PMID: 21416464
  11. Johnston RJ, Comps-Agrar L, Hackney J, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell. 2014;26:923-937. PMID: 25465800
  12. Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol. 2016;27:1492-1504. PMID: 27207108
  13. Chen DS, Mellman I. Oncology meets immunology: the cancer immunity cycle. Immunity. 2013;39:1-10. PMID: 23890059

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