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Research progress of tumor immunotherapy targeting TIGIT
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Research progress of tumor immunotherapy targeting TIGIT
In the past decade, the discovery of T-cell immune checkpoints and the development of monoclonal antibodies that inhibit checkpoints have dramatically changed the outcomes of immunotherapy.
However, PD-1 therapy still shows long-term, durable responses in only 10-30% of patients, lack of response in most populations, and acquired resistance as well as immune-related adverse events ( IRAEs ) are also huge obstacles.
One of the mechanisms to overcome the limitations of PD-1 therapy is to target other immune checkpoints associated with the tumor microenvironment.
Currently, TIGIT is considered to be one of the most promising and potential targets, and multiple lines of evidence support the pivotal role of TIGIT in limiting both adaptive and innate immunity in tumors.
Recently, the transaction between Baekje and Junshi has made TIGIT a hot spot again.
Below, the editor will take you to review the role of TIGIT in tumor immunology and the current research progress of TIGIT-based tumor immunotherapy.
TIGIT functional axis and ligands
TIGIT ( also known as WUCAM, Vstm3, VSIG9 ) is a receptor of the Ig superfamily that plays a key role in limiting adaptive and innate immunity.
TIGIT is involved in a complex regulatory network involving multiple IRs ( eg, CD96/TACTILE, CD112R/PVRIG ), a competing costimulatory receptor ( DNAM-1/CD226 ), and multiple ligands ( eg, CD155, CD112 ) ).
Thus, with some similarities to the CD28/CTLA-4/CD80/CD86 pathway, inhibitory and costimulatory receptors compete for binding to the same ligand.
TIGIT is expressed by activated CD8+ T and CD4+ T cells, natural killer ( NK ) cells, regulatory T cells ( Tregs ) and follicular helper T cells.
In stark contrast to DNAM-1/CD226, TIGIT is weakly expressed in naive T cells. In cancer, TIGIT is co-expressed with PD-1 on mouse and human tumor antigen-specific CD8+ T cells and CD8+ tumor-infiltrating lymphocytes ( TILs ). It is also co-expressed with other IRs, such as TIM-3 and LAG-3 on CD8+ T cells depleted in tumors.
Furthermore, TIGIT was highly expressed in peripheral blood mononuclear cells of healthy people and cancer patients and was further upregulated in the TME.
TIGIT binds two ligands, CD155 and CD112, which are expressed on monocytes, dendritic cells ( DCs ), and many non-hematopoietic cells, including tumor cells of different histological types .
TIGIT binds CD155 with higher affinity than competing receptors CD226 and CD96.
TIGIT binds weakly to CD112, and CD112R binds CD112 with higher affinity than CD226. Interestingly, the expression of CD155 is increased upon activation of the reactive oxygen species-dependent DNA damage response, which regulates NK cell interactions with T cells and myeloid-derived suppressor cells ( MDSCs ).
In addition, Fap2 protein from Fusobacterium nucleatum , an anaerobic Gram commensal bacteria associated with colorectal cancer, can directly bind to TIGIT but not CD226, thereby inhibiting NK cells and T cell mediators induced tumor response.
These findings suggest that the gut microbiome modulates innate immune responses in a TIGIT-mediated manner.
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 inhibitory motifs conserved in mice and humans: Immunoreceptor tyrosine-based inhibitory motif ( ITIM ) and Ig tail tyrosine-like ( ITT ) motif.
The crystal structure of TIGIT bound to CD155 shows that two TIGIT/CD155 dimers form a heterotetramer with a TIGIT/TIGIT cis homodimer at the core, with each TIGIT molecule bound to one CD155 molecule.
This cis-trans receptor aggregation mediates cell adhesion and signaling.
In mice, phosphorylation of ITIM ( Y227 ) or ITT-like motif residues ( Y233 ) can trigger TIGIT inhibitory signals.
However, in the human NK cell line YTS, TIGIT/CD155 binding initiates a major inhibitory signal through an ITT-like motif, while the ITIM motif mediates a minor inhibitory signal.
After activation by TIGIT/CD155 binding, the ITT-like motif is phosphorylated at Tyr225 and binds to the intracytoplasmic signaling molecules Grb2 and β-arrestin 2 to recruit inositol-containing SH2 phosphatase-1 ( SHIP-1 ). SHIP-1 impedes phosphoinositide 3-kinase and mitogen-activated protein kinase signaling.
SHIP-1 also inhibits the activation of TRAF6 and NF-κB, resulting in decreased IFN-γ production by NK cells.
Mechanism of action of TIGIT
TIGIT potentially suppresses innate and adaptive immunity through multiple mechanisms. First, in mouse models, TIGIT indirectly impedes T cell function by binding to CD155 on DCs.
Binding of TIGIT to DCs induces CD155 phosphorylation and triggers a signaling cascade that promotes the formation of immune-tolerant DCs, reduces IL-12 production and leads to an increase in IL-10.
Second, TIGIT directly exhibits an intrinsic inhibitory effect on 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 CD155-expressing MDSCs reduced the phosphorylation of ZAP70/Syk and ERK1/2, and decreased the cytolytic capacity of NK cells.
Third, multiple lines of evidence suggest that TIGIT hinders CD155-mediated activation of CD226.
CD226 is a costimulatory receptor that is widely expressed on immune cells, including T cells, NK cells, monocytes, etc., as well as platelets.
TIGIT binds CD155 with higher affinity than CD226, thereby limiting CD226-mediated activation.
In addition, TIGIT also directly binds CD226 in cis on cells, disrupting its ability to bind to the homodimer of CD155.
Fourth, the balance of TIGIT/CD226 expression regulates the effector functions of T cells and NK cells.
In TCR-activated CD4+ T cells, knockdown of TIGIT expression with shRNA increased T-bet expression and IFN-γ production; conversely, CD226 knockdown 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 many Treg gene markers, including Foxp3, Helios, neuronilin-1, CTLA-4, PD-1, and LAG-3, both in the periphery and at the tumor site.
TIGIT+Tregs also inhibited the pro-inflammatory responses of Th1 and Th17, but not Th2. After TIGIT activation, TIGIT++ Tregs produce IL-10 and fibrinogen-like protein 2, which mediate T cell suppression. Image
Clinical progress of TIGIT-targeted drugs
Currently, targeting the TIGIT-PVR pathway is becoming more and more important, and some biotech/pharmaceutical companies are working on developing anti-TIGIT antibodies or double-antibodies.
As of the end of 2021, a total of 23 TIGIT-targeting mAbs or doublets are in commercial development and are in various stages of clinical development.
Looking at the world, there are many leading pharmaceutical companies such as Roche, Bristol-Myers Squibb and Merck. Among them, Roche and Merck with the fastest progress are both in clinical phase III.
On December 20, 2021, BeiGene and Novartis reached a cooperation agreement, and Novartis will obtain the rights and interests of BeiGene’s TIGIT antibody in the United States, Canada, many European countries and Japan.
To this end, Novartis will make an upfront payment of $300 million, additional payments of $600 million or $700 million, milestones of $1.895 billion, and a 20-25 percent share of sales.
In fact, since 2021, major overseas pharmaceutical companies have emerged in an endless stream of blockbuster deals around TIGIT. On May 19, Bristol-Myers Squibb announced the acquisition of Agenus’ preclinical TIGIT double-antibody AGEN1777 with a down payment of 200 million and a potential mileage of 1.36 billion;
on June 14, GlaxoSmithKline and iTeos Therapeutics reached a cooperation agreement to introduce the latter For the TIGIT monoclonal antibody EOS-448, GlaxoSmithKline paid $625 million in advance + $1.45 billion in milestones.
Obviously, the arms race for TIGIT monoclonal antibody has gradually heated up.
Considerations during development
Several factors, such as the source of the antibody backbone ( mouse, chimeric, humanized or fully human ), the IgG backbone of the antibody, the FcγR binding state and dosage, play a key role in the development and eventual clinical success of the antibody.
The source of antibodies used for therapeutic applications can significantly impact the clinical success of the molecule.
To date, all approved immune checkpoint blockers are either humanized or fully human, and most anti-TIGIT antibodies in clinical development are fully human.
FcγR binding state
Almost all commercially developed immune checkpoint blocking antibodies have an IgG backbone.
IgG-based antibodies are known to interact with FcγRs on innate effector immune cells through their Fc regions 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 role in immune checkpoint blocker activity is not fully understood.
In clinical development, the FcyR-binding region of anti-TIGIT antibodies is active in some molecules and inactive in others.
According to public information, tiragolumab, ociperlimab, vibostolimab, EOS-448, etigilimab and AGEN-1307 have active FcγR binding regions, while domvanalimab and BMS-986207 have inactive FcγR binding regions.
It remains to be seen whether the presence or absence of the FcγR-binding region in the antibody will have an impact on the clinical efficacy of anti-TIGIT antibodies.
Various factors, including affinity, pharmacodynamic factors, and pharmacokinetic factors all affect the maximum tolerated dose and the dose at which the drug is expected to produce the greatest effect.
The results of phase I studies in multiple clinical programs have shown that anti-TIGIT antibodies are well tolerated.
The study used different dose ranges of the antibody, administered every two weeks ( Q2W ) or every three weeks ( Q3W ).
During clinical development, no dose-limiting toxicity has been recorded with either anti-TIGIT antibody monotherapy or in combination with anti-PD-1 antibody, suggesting that molecules targeting this target have a broad therapeutic index.
The clinical activity observed after anti-TIGIT antibody monotherapy is low or even zero, indicating the need for combination therapy with anti-PD-1/PD-L1 or other drugs.
Anti-TIGIT antibodies were found to be generally well tolerated when used as monotherapy and in combination with PD-1/PD-L1 blockers.
The most common adverse events reported by more than 10% of patients included fatigue and pruritus, both grade 1.
Two grade 2 events, anemia and diarrhea, were reported in two patients receiving vibostolimab monotherapy.
No adverse events of grade 3 or higher were reported with anti-TIGIT antibody monotherapy.
Challenges and Prospects
TIGIT is a promising target for tumor immunotherapy, especially in combination with PD-1 blockade. However, as TIGIT-based clinical trials in cancer patients progress, we need to address many key questions and challenges.
First, what is the mechanism of action of TIGIT blockers in cancer patients? Are these effects primarily mediated by their direct activity in CD8+ T cells, Tregs, or both?
Can TIGIT block the reprogramming of APCs in the TME to increase T cell priming or activation? Do these effects vary by disease stage?
Can TIGIT blockade mediate NK cell-mediated responsiveness to MHC class I-deficient tumors in vivo, and does this provide an opportunity for clinical benefit in patients with PD-1-refractory cancers?
And, apart from dual PD-1/TIGIT blockers, are there any potential synergistic effects of CD112R or CD96 blockade, as shown in mouse tumor models and in vitro studies?
In this regard, we must remember that the role of CD96 as an IR remains controversial. Furthermore, evidence that CD112R blockade can potentially enhance autologous human tumor antigen-specific CD8+ T cells is still missing.
In addition, CD226 plays an important regulatory role in PD-1/TIGIT dual blockade.
Downregulation of CD8+ T cells and NK cells in the TME may be a major obstacle to the success of PD-1/TIGIT dual blockade.
Therefore, it is necessary to design new strategies to increase the expression and signaling of CD226 to prevent its downregulation in the TME.
Notably, an ongoing clinical trial is testing an anti-CD226 agonist (NCT04099277) in multiple cancers.
However, due to the role of CD226 in mediating platelet adhesion and activation, potential hematological adverse events require careful monitoring.
Finally, clinical trials using different engineered Fc anti-TIGIT mAbs may help determine the role of FcγR synergy in TIGIT blockade.
In conclusion, TIGIT has entered clinical trials as an immunotherapy target only 10 years after its discovery.
With the in-depth study of TIGIT-mediated immune response regulation, it will help to design optimal combination strategies of TIGIT blockers for cancer patients, and will also help to develop targeted TIGIT therapy to treat other chronic diseases that express this protein. disease.
references: Research progress of tumor immunotherapy targeting TIGIT
1. TIGIT in cancer immunotherapy. J Immunother Cancer 2020;8:e000957.
2. Targeting TIGIT for Immunotherapy of Cancer: Update on Clinical Development. Biomedicines. 2021 Sep; 9(9):1277.
Research progress of tumor immunotherapy targeting TIGIT
(source:internet, reference only)