TIGIT is considered to be one of the most promising and potential targets, and a variety of evidence supports that TIGIT plays a key role in limiting the adaptive and innate immunity of tumors. This article will review the role of TIGIT in tumor immunology and the current research progress in TIGIT-based tumor immunotherapy.
TIGIT structure and signaling pathway
TIGIT consists of an extracellular immunoglobulin (Ig) variable domain, a type 1 transmembrane domain, and an intracellular domain with two conserved inhibitory moieties in mice and humans: the immunoreceptor tyrosine-based inhibitory motif (ITIM) and the Ig tyrosine tail (ITT)-like motif. The crystal structure of TIGIT bound to CD155 shows that two TIGIT/CD155 dimers form a heterotetramer with a TIGIT/TIGIT cis-homologous dimer as the core, with each TIGIT molecule bound to one CD155 molecule. This cis-trans receptor clustering mediates cell adhesion and signaling.
In mice, phosphorylation of ITIM (Y227) or ITT-like motif residues (Y233) triggers TIGIT inhibition signals. However, in the human NK cell line YTS, TIGIT/CD155 binding activates the main inhibitory signal via an ITT-like motif, while the ITIM motif mediates a smaller inhibitory signal. After activation of the TIGIT/CD155 binding, ITT-like motifs are phosphorylated at Tyr225 and bind to intracytoplasmic signaling molecules Grb2 and β-arrestin 2 to recruit inositol containing SH2 phosphatase-1 (SHIP-1). SHIP-1 impedes signal transduction by phosphoinositide 3-kinase and mitogen-activated protein kinase. SHIP-1 also inhibits the activation of TRAF6 and NF-κB, resulting in reduced IFN-γ production by NK cells.
The mechanism of TIGIT
TIGIT potentially inhibits innate and adaptive immunity through a variety of mechanisms.
First, in mouse models, TIGIT indirectly blocks T cell function by binding to CD155 on DCs. The binding of TIGIT to DCs induces CD155 phosphorylation and triggers a signaling cascade that promotes the formation of immunotolerant DCs, reduces IL-12 production, and leads to an increase in IL-10.
Second, TIGIT directly shows the intrinsic inhibitory effect of immune cells. In mice and humans, TIGIT inhibits NK cell degranulation, cytokine production, and NK cell-mediated cytotoxicity of CD155+ tumor cells. The interaction of TIGIT+ NK cells with MDSCs expressing CD155 reduces the phosphorylation of ZAP70/Syk and ERK1/2, and decreases the cytolytic ability of NK cells.
Third, much evidence suggests that TIGIT blocks CD155-mediated CD226 activation. CD226 is a costimulatory receptor that is widely expressed in immune cells, including T cells, NK cells, monocytes, and platelets. TIGIT binds CD155 with a higher affinity than CD226, thereby limiting CD226-mediated activation. In addition, TIGIT cis-binds CD226 directly on cells, disrupting its ability to bind to the homologous dimer of CD155.
Fourth, the balance of TIGIT/CD226 expression regulates the effector function of T cells and NK cells. In TCR-activated CD4+ T cells, the knockout of TIGIT expression by shRNA increases T-bet expression and IFN-γ production. In contrast, CD226 gene knockout decreased T-bet expression and IFN-γ production. T cell-mediated tumor rejection can be enhanced by balancing CD226 and TIGIT in CD8+ T cells.
Fifth, TIGIT acts on Tregs to enhance immunosuppressive function and stability. Compared with TIGIT− Tregs, TIGIT+ Tregs upregulated a number of Treg gene markers, including Foxp3, Helios, neuropilin-1, CTLA-4, PD-1, and LAG-3, in peripheral and tumor sites. TIGIT+ Tregs also inhibit the pro-inflammatory response of Th1 and Th17, but not Th2. Upon activation of TIGIT, TIGIT+ Tregs produce IL-10 and fibrinogen-like protein 2, which mediate T cell inhibition.
Clinical progress in drugs targeting TIGIT
Currently, targeted TIGIT-PVR pathways are becoming increasingly important, and some biotechnology/pharmaceutical companies are working on developing anti-TIGIT antibodies or dual antibodies. At the end of 2021, a total of 23 monoclonal or dual antibodies targeting TIGIT are in commercial and clinical development. Looking around the world, developers such as Roche, Bristol Myers Squibb, Merck, and other leading pharmaceutical companies are involved. Among them, the fastest progress is made by Roche and Merck, both in clinical phase III.
Factors to be considered in the development
Several factors may impact the development and ultimate clinical success of the antibody.
a. Source
The source of antibodies used for therapeutic applications can significantly influence the clinical success of a molecule. To date, all approved immune checkpoint inhibitors are either humanized or fully human, and most anti-TIGIT antibodies in clinical development are fully human antibodies.
b. FcγR binding state
Almost all commercially developed immune checkpoint inhibiting antibodies have an IgG skeleton. IgG-based antibodies are known to interact with FCγR on innate effector immune cells through their Fc region and induce antibody-dependent cellular cytotoxicity (ADCC) in target cells. ADCC is the most common factor considered in the development of therapeutic antibodies, but its effect on immune checkpoint inhibitor activity is not yet completely understood.
In clinical development, the FCγR binding region of anti-TIGIT antibodies is active in some molecules and inactivate in others. According to the public data, tiragolumab, ociperlimab, vibostolimab, EOS-448, etigilimab, and AGEN-1307 have active FCγR binding regions, while domvanalimab and BMS-986207 have inactive FCγR binding region. It remains to be seen whether the presence or absence of the FCγR binding region in antibodies has any effect on the clinical efficacy of anti-TIGIT antibodies.
c. Dose
In clinical development, dose-limiting toxicity is not documented in any monotherapy with anti-TIGIT antibodies or in combination with anti-PD-1 antibodies, indicating that molecules targeting this target have a broad therapeutic index. The observed clinical activity of anti-TIGIT antibodies after monotherapy is low to zero, indicating the requirement for combination therapy with anti-PD-1 /PD-L1 or other agents.
d. Security
Anti-TIGIT antibodies are generally found to be well tolerated when used as monotherapy and in combination with PD-1/PD-L1 inhibitors. The most common adverse events reported by more than 10% of patients include fatigue and itching, both grade 1. Two grade-2 events, anemia and diarrhea, are reported in two patients treated with vibostolimab monotherapy. No grade 3 or above adverse events are reported for anti-TIGIT antibody monotherapy.
Conclusion
Only 10 years after its discovery, TIGIT has entered clinical trials as a target for immunotherapy. Further research on TIGIT-mediated immune response regulation will contribute to the strategy design of TIGIT inhibitors for cancer patients, as well as the development of therapies targeting TIGIT for other chronic diseases expressing this protein.