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Diagram of TIGIT pathway expressed between a T cell and tumor cell

T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), an immune checkpoint receptor, can suppress T-cell activation and promote T-cell exhaustion. Inhibition of TIGIT may increase cytotoxic T-cell proliferation and function.

  • TIGIT is an immune checkpoint receptor on cytotoxic, memory, and Tregs, as well as NK
    • On cytotoxic T cells and NK cells, interaction of TIGIT with either of its 2 ligands, CD155 (PVR) and CD112 (Nectin2), suppresses immune activation1,2
    • When TIGIT is expressed on Tregs, however, this interaction enhances their ability to suppress the immune response3
  • The suppressive effect of TIGIT is counterbalanced by the immune-activating receptor CD226 (also called DNAM1), which is also expressed on cytotoxic T cells and NK cells and competes with TIGIT to bind to CD155 and CD1124,5
    • The inhibitory signal provided by TIGIT overpowers DNAM1’s ability to stimulate T-cell activation5
  • In cancer, tumor cells exploit the inhibitory TIGIT pathway to avoid immune-mediated destruction
  • Based on preclinical studies, inhibition of TIGIT alone or in combination with other checkpoint inhibitors increases the proliferation and function of cytotoxic T cells7,9-11
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How does TIGIT overpower cytotoxic T-cell activity?

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1. Yu X, Harden K, Gonzalez LC, et al. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol. 2009;10(1):48-57. 2. Stanietsky N, Simic H, Arapovic J, et al. The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. Proc Natl Acad Sci U S A. 2009;106(42):17858-17863. 3. 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(4):569-581. 4. Bottino C, Castriconi R, Pende D, et al. Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. J Exp Med. 2003;198(4):557-567. 5. Lozano E, Dominguez-Villar M, Kuchroo V, Hafler DA. The TIGIT/CD226 axis regulates human T cell function. J Immunol. 2012;188(8):3869-3875. 6. Goding SR, Wilson KA, Xie Y, et al. Restoring immune function of tumor-specific CD4+ T cells during recurrence of melanoma. J Immunol. 2013;190(9):4899-4909. 7. 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(6):923-937. 8. Chauvin J-M, Pagliano O, Fourcade J, et al. TIGIT and PD-1 impair tumor antigen-specific CD8+ T cells in melanoma patients. J Clin Invest. 2015;125(5):2046-2058. 9. Joller N, Hafler JP, Brynedal B, et al. Cutting edge: TIGIT has T cell-intrinsic inhibitory functions. J Immunol. 2011;186(3):1338-1342. 10. Hung AL, Maxwell R, Theodros D, et al. TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM. Oncoimmunology. 2018;7(8):e1466769. doi:10.1080/2162402X.2018. 1466769. 11. Kurtulus S, Sakuishi K, Ngjow S-F, et al. J Clin Invest. 2015;125(11):4053-4062.