**5.1 General description**

TIGIT, also known as V-set and transmembrane domain containing (Vstm), *Washington University cell adhesion molecule (*wucam) or *V-set and immunoglobulin domain-containing protein 9* (VSIG9), is a receptor of the Ig superfamily. It is an important player in adaptive as well as innate immunity regulation [66]. TIGIT is expressed on activated T cells, both in TH and CTL subsets, NK cells, Tregs, and follicular TH [67]. In cancer, TIGIT is often co-expressed with PD-1 on tumor-antigenspecific CD8+ T cells and C8+ tumor-infiltrating lymphocytes (TILs) in human and mice [68]. In addition, it is co-expressed with Tim-3 and LAG-3 on exhausted CTLs in tumors [66]. When homozygously knocked out, TIGIT -/- mice do not develop

*Immune Checkpoints: The Rising Branch in Cancer Immunotherapy DOI: http://dx.doi.org/10.5772/intechopen.108656*

autoimmunity. But when compared with wild-type mice, TIGIT -/- mice suffer severe autoimmune encephalitis, after immunized with myelin oligodendrocyte glycoprotein. This supports the role of TIGIT as a negative regulator of T cell functions [69].

Structurally, TIGIT is composed of an extracellular immunoglobulin variable domain, a type I transmembrane domain, a short intracellular domain encompassing one immunoreceptor tyrosine-based inhibitory motif (ITIM) and one immunoglobulin tyrosine tail (ITT)-like motif. The immunoglobulin variable domain and members of poliovirus receptor (PVR)-like family such as DNAM-1, CD96, CD155, CD111, CD112 (PVR-related 2 (PVRL2), nectin-2, CD113 (poliovirus receptor-related 3 (PVRL3), nectin-3), and PVRL4 share sequence homology in common [70].

#### **5.2 TIGIT signaling pathways**

TIGIT has three ligands namely CD155, CD112, and CD113. These ligands belong to nectin and nectin-like (NECL) molecules that mediate cell adhesion, cell polarization, and tissue organization [71]. Among these, CD155 is the main receptor for TIGIT. Both homodimerize and upon engagement form heterotetramers. CD155 is mainly expressed on dendritic cells (DCs), T cells, B cells, and macrophages but also in non-haematopoietic tissues [72]. Following the ligation of TIGIT:CD155, inhibitory signaling is initiated via ITT-like motif. Amino acid tyrosine at position of 225 (tyr225) of the ITT-like motif is phosphorylated and coupled onto cytosolic adapter of growth factor receptor-bound protein 2 (Grb2) and β-arrestin 2 to facilitate recruitment of Src homology-2 (SH2)-containing inositol phosphatase-1 (SHP-1). This recruitment thwarts phosphoinositide 3 kinase and mitogen-activated protein kinase signaling, thus reducing killing capacity in NK cells [73]. SHIP-1 also impairs TRAF6 and nuclear factor ƙ light-chain-enhancer of activated B cells (NF-ƙB) which impedes production of IFN-γ by NK cells [74].

Other than CD155 as the highest binding magnitude ligand, CD112 and CD113 are also reported to bind well to TIGIT, but at lesser magnitude . While CD112 shows a broad range of expression in both hematopoietic and non-hematopoietic tissues, CD113 is restricted to non-hematopoietic tissues. Their overexpression is observed in in several malignancies [70]. CD112R has recently been found as a receptor for CD112 other than TIGIT. It was reported that the combined CD112R and TIGIT blockade allowed diffusion of CD4+ T cells and increased the productions of cytokines such as IFN-γ, IL-2, IL-5, IL-10, and IL-13. Moreover, blockade to these two checkpoints led to restored cytotoxicity and expansion of CD8+ T cells [75].

#### **5.3 TIGIT's bright future in cancer immunotherapy**

TIGIT is relatively new discovered checkpoint molecule that seems to be a promising target in immune checkpoint-based cancer immunotherapy. This checkpoint was evidently shown to prevent tumor antigen release by CD8+ T cells and impair T cell priming by DCs or obstruct cancer cells killing by CD8+ T cells. And it is now under investigation in various clinical trials [72].

Recently, six human-anti-TIGIT monoclonal antibodies (mAbs) of the IgG1 isotype are being investigated in clinical trials. OncoMed Pharmaceuticals (US) produced Etigilimab (OMP-313M32). The mouse version of this 313R12 mAb was reported to function similar to etigilimab, i.e. suppression of syngeneic colon and kidney tumors in immune competent mice and improved TH1-type response. Now, etigilimab commences its pharmacokinetics assessment in a Phase I trial. Furthermore,

Arcus Bioscience's AB154 and Merck's MK-7684 drugs, which are designed as monotherapy for advanced solid cancers and solid cancers, respectively, are in Phase 1 trials. Merck's MK-7684 is also being tested in combination with pembrolizumab (anti PD-1 mAb). Tiragolumab by Genentech/Roche is also in Phase II trial designed as combination therapy with atezolumab (anti-PD-1 mAb) for advanced or metastatic non-small cell lung cancer (NSCLC). Bristol-Myers Squibb bulks up the trials for TIGIT by producing BMS-986207 which is IgG1 mAb (FcγR-null) anti-TIGIT to target advanced or metastatic solid cancers. The Fc portion on the IgG of this mAb has been mutated to avoid ligating to Fcγ receptor (FcγR) because Fcγ-dependent mechanisms were found to inhibit antitumor activity of anti-PD-1 mAbs. With similar strategy (IgG1 mAb and FcyR-null), Astellas Pharma (Potenza Therapeutics) has also designed ASP 8374 [72].
