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TIGIT
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
cells - 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
- Increased presence of TIGIT and its ligands is associated with impaired DNAM1 signaling and T-cell exhaustion, leading to a progressive loss of T-cell function5-8
- 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
How does TIGIT overpower cytotoxic T-cell activity?
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REFERENCES–TIGIT
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.