1. Introduction

The idea of using immune response against abnormal cells in the body to treat cancer has been tested in the past few decades and evolved from using recombinant cytokines to adoptive cell transfer ^[1][2][1,2]. The first generation of immunotherapies like high-dose interleukin-2 were limited by low response rates and high incidence of serious adverse events, but the durability of response encouraged further research in the field ^[3][4][5][3,4,5]. Discovery of checkpoints of T-cell activation and development of monoclonal antibodies targeting the checkpoints dramatically changed the outcomes of immunotherapy ^{[6][7][8][9][10][11][12]}[6,7,8,9,10,11,12]. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) were the early targets that were discovered and characterized in the late 1980s and early 1990s, respectively ^{[13][14][15][16][17][18][19]}[13,14,15,16,17,18,19]. Both CTLA-4 and PD-1 have been shown to be reliable targets, and to date, seven drugs have been approved for different types of cancers, such as melanoma and lung cancer ^{[20][21][22][23][24]}[20,21,22,23,24]. In addition to monotherapy, combination of CTLA-4 and PD-1 blockers is also approved for treatment of multiple cancer types [23]. While the CTLA-4 and PD-1 blockers had decent and durable response rates, a large fraction of patients did not respond to the treatment, and the incidence of serious adverse events was high in the responding patients ^[25][26][27][25,26,27]. The need for safer targets that can be blocked or activated to achieve reasonable anti-tumor response with manageable adverse events and that can be combined with PD-1/PD-L1 blockers or other immune checkpoint blockers led to the identification of T-cell immunoglobulin and ITIM domain (TIGIT), an inhibitory immune checkpoint, and the development of anti-TIGIT antibodies.

TIGIT is considered as an important target mainly because of its expression profile (natural killer cells (NK cells), cytotoxic CD8 + T cells and regulatory T cells (Tregs) [28]. More importantly, the phenotype of Tigit −/− mouse was reported to be mild, and the knockout mice did not spontaneously develop autoimmunity, indicating a comparatively milder safety profile [29].

2. Tigit

TIGIT expression is mainly seen on resting CD4 + CD25 hi Treg cells, activated T cells, NK cells, NKT cells, and memory T cells. Naïve CD4 + T cells do not express TIGIT, but its expression is induced at mRNA levels upon activation ^[30][35]. TIGIT has been reported as marker for CD8+ T-cell exhaustion and is also a characteristic marker for Tregs in the tumor microenvironment ^{[7][28][29][31][32]}[7,28,29,37,38].

CD155 expression is mainly reported on DCs, T cells, B cells, and macrophages, whereas CD112 is widely expressed on both hematopoietic and non-haematopoietic tissues, including bone marrow, lung, pancreas, and kidney ^[33][34][40,41]. CD113 expression is limited to non-hematopoietic tissues, such as lung, liver, testis, kidney, and placenta ^[35][42]. Several human cancers are reported to overexpress CD155 and CD112 ^[36][37][38][43,44,45]. Interestingly, interferon-γ (IFN- γ) was shown to up-regulate the expression of CD155 on human vascular endothelial cells, a mechanism similar to induction of PD-1/PD-L1 pathway ^[39][46].

TIGIT is a negative regulator of immune response known to bind to PVR ligands with greater affinity and outcompete the costimulatory receptors, CD226 and CD96, expressed on T cells, thereby inhibiting the activation, proliferation, and differentiation of T cells ( Figure 1 ). Further, TIGIT engagement ensures the survival of inhibited T cells by activating cell survival pathways. [7]. TIGIT activation on NK cells was shown to inhibit cytotoxic granule polarization and IFN-γ production and decrease NK cell cytotoxicity ^[40][41][30,47]. In addition, TIGIT interaction on Tregs skews the cytokine balance, suppresses Th1 or Th17 phenotype, and induces Th2 phenotype ^[29][42][29,48]. However, unlike CTLA-4 and PD-1, which, when knocked out in mice, are known to manifest as severe and spontaneous autoimmune phenotype ^{[17][43][44][45]}[17,49,50,51], TIGIT knock-out mice do not spontaneously develop autoimmune phenotype, indicating mild to moderate control of TIGIT over immune response [29].

Figure 1. Role of TIGIT in regulation of immune response. TIGIT competitively inhibits binding of CD226 to CD155 and impairs the CD226-mediated activation of T cells and NK cells. Binding of TIGIT to its ligand CD155 results in activation of inhibitory signals in T cells and NK cells. TIGIT binding to CD155 on APCs results in IL-10 production, decreased IL-12 production (not shown in the illustration), and indirect inhibition of T cells. Finally, TIGIT signaling enhances the immunosuppressive functions of Tregs.

Even before the discovery of TIGIT, its ligands were known to be upregulated on the surface of tumor cell surface. Expression of nectin family of proteins and their role in cell adhesion and survival was reported in tumors from epithelial origin, such as non-small cell lung cancer, colon cancer, and metastatic neuroblastoma, and also tumors from hematopoietic origin, such as myeloid leukemia ^{[36][46][47][48][49]}[43,52,53,54,55]. High expression of CD155 was shown to be an independent prognostic marker and predictor of poor clinical outcome in breast cancer patients ^[50][56]. The recently discovered ligand for TIGIT, nectin 4, was shown to be overexpressed in breast, bladder, lung, and pancreatic cancers ^[51][57]. On the other hand, TIGIT expression was also reported to be upregulated on lymphocytes in tumor microenvironment. Studies showed TIGIT expression on CD8 + , CD4 + T cells, and NK cells paralleled to that of PD-1 in hepatocellular, lung, and colorectal cancers and in Hodgkin’s lymphoma ^{[52][53][54][55][56][57][58][59]}[58,59,60,61,62,63,64,65].

3. Anti-Tigit Antibodies in Development