TIGIT

TIGIT is the acronym for "T cell immunoreceptor with Ig and ITIM domains" and refers to an inhibitory immunoglobulin receptor that has a tyrosine-based inhibitory motif domain (ITIM). TIGIT is expressed by CD8 +, CD4 + T cells (mainly regulatory T cells [Tregs]) and NK cells (Kong Y et al.2016). TIGIT binds with high affinity to CD155 on dendritic cells, on macrophages, and with lower affinity also to CD112 (Nectin-2). TIGIT is encoded by the gene of the same name located on chromosome 3: 114.28 - 114.31 and can be considered an immune checkpoint.

TIGIT and CD96 together with the co-stimulatory receptor CD226 form a pathway (this is analogous to the CD28/CTLA-4 pathway ) in which shared ligands and different receptor/ligand affinities fine-tune the immune response. This pathway is referred to as the: CD226/TIGIT-PVR pathway. Through this pathway, TIGIT regulates T cell-mediated immunity.

TIGIT represents the immunosuppressive signaling counterpart of DNAM-1, with which it competes for binding to CD112 (Nectin-2) and CD155 (PVR). TIGIT exhibits higher binding affinity for CD155 than for DNAM-1, implying that expression of TIGIT on tumor-infiltrating lymphocytes is sufficiently strong to shift the immune response toward an immunosuppressed phenotype, thereby abrogating the cytotoxicity of NK cells and CD8 + T cells (Kong Y et al. 2016). In addition, TIGIT has been described to prevent homodimerization of DNAM-1, thereby preventing its signaling and subsequent antitumor response. Expression of TIGIT on cytotoxic cells prevents their activation and degranulation through competition with DNAM-1, and its expression on Tregs induces suppression of other inflammatory cell types, via regulation of anti-inflammatory cytokines. Furthermore, TIGIT and PD-1 have been shown to be overexpressed on tumor antigen-specific (TA-specific) CD8+ T cells and CD8+ tumor-infiltrating lymphocytes (TILs) from individuals with melanoma.

Blockadeof TIGIT: Blockade of TIGIT and PD-1 resulted in increased cell proliferation, cytokine production, and degranulation of TA-specific CD8+ T cells and TIL CD8+ T cells. Co-blockade of TIGIT and PD-1 signaling pathways triggers tumor rejection in preclinical mouse models.

Clinical studies: The number of studies dealing with TIGIT has increased in recent years, allowing researchers to establish a catalog of TIGIT expression in tumors. Evidence shows that TIGIT is expressed on lymphoid cells in non-small cell lung cancer (NSCLC) , melanoma, breast cancer, colon adenocarcinoma (COAD), AML, and multiple myeloma (MM) (Wu MR et al. 2015; Harjunpää H et al. 2020; Stålhammar G et al. 2019; O'Brien SM et al. 2019). To date, several clinical trials with anti-TIGIT antibodies are ongoing.

Oncomed Pharmaceutical's anti-TIGIT mAb etigilimab (OMP-313M32) was tested for safety and pharmacodynamics in a phase I dose-escalation study (NCT031119428) alone or in combination with anti-PD1(nivolumab) for the treatment of advanced solid tumors. Etigilimab appeared to be well tolerated by patients after phase Ia; however, this phase Ib trial was discontinued for sponsor reasons.

Other phase I and II clinical trials are ongoing: tiragolumab (Genentech Roche) for the treatment of NSCLC, AB154 (Arcus Biosciences) for the treatment of advanced solid malignancies, MK-7684 (Merck) for the treatment of solid tumors, BMS986207 (Bristol Myers Squibb) for the treatment of advanced and metastatic solid tumors, and ASP8374 (Astellas Pharma, Potenza Therapeutics) for the treatment of advanced or metastatic solid malignancies.

The immunological synapse formed by the interaction of CD155 (PVR)and Nectin-2 with their receptors DNAM-1, TIGIT and CD96 represents a complex interaction system. The CD155(PVR)-TIGIT axis consists of two main ligands: CD155 (PVR)and Nectin-2 interacting with three receptors (DNAM-1, TIGIT and CD96). When developing an immunological therapeutic approach with antagonistic mAbs, it is necessary to consider the multiple interactions and alternative binding that may occur. When considering the inhibitory nature of its signal transduction, blocking TIGIT interactions with its ligands is obvious. CD155 (PVR)is capable of binding both inhibitory and activating receptors of the nectin-like protein family. Studies show that using anti-PVR-mAbs to avoid its interactions with inhibitory receptors allows restoration of the antitumor response ( Stamm H et al. 2018). This makes CD155 (PVR)an interesting checkpoint blockade target. Furthermore, CD155 (PVR)is being investigated in clinical trials as an entry point for oncolytic polioviruses.

DNAM-1 will certainly be investigated in the future regarding its function in the activation of cytotoxic lymphocytes also as a target for immunotherapy. Thus, strategies aimed at stimulating the DNAM-1 pathway are being developed, including the use of agonistic mAbs or DNAM-1-based cell transfer. Nectin-2 remains poorly explored as a target for immunotherapy, primarily due to its weaker affinity for both DNAM-1 and TIGIT, as well as its lack of retro-signaling. Nevertheless, nectin-2 represents a potential target, particularly in tumors where its expression is elevated. CD96 could also represent a target for immune checkpoint blockade if its function were more sharply defined in humans.

1. Dougall WC et al (2017) TIGIT and CD96: New checkpoint receptor targets for cancer immunotherapy. Immunol Rev 276:112-120.

2. Georgiev HG et al (2018) Coming of Age: CD96 Emerges as Modulator of Immune Responses. Front. Immunol 9: 1072.

3. Harjunpää H et al (2020) TIGIT as an emerging immune checkpoint. Clin Exp Immunol 200:108-119.
4. Johnston RJ et al (2014) The immunoreceptor TIGIT regulates antitumor and antiviral CD8 + T cell effector function. Cancer Cel 26:923-937.
5. Kong Y et al.(2016) T-Cell Immunoglobulin and ITIM Domain (TIGIT) Associates with CD8 + T-Cell Exhaustion and Poor Clinical Outcome in AML Patients. Clin Cancer Res 22:3057-3066.
6. O'Brien SM et al (2019) Function of human tumor-infiltrating lymphocytes in early-stage non-small cell lung cancer. Cancer Immunol Res 7:896-909.
7. Stålhammar G et al (2019) Expression of immune checkpoint receptors indoleamine 2,3-dioxygenase and T cell Ig and ITIM domain in metastatic versus nonmetastatic choroidal melanoma. Cancer Med 8:2784-2792.
8. Stamm H et al. (2018) Interaction of PVR/PVRL2 with TIGIT/DNAM-1 as a novel immune checkpoint axis and therapeutic target in cancer. Mamm Genome 29:694-702.
9. Stanietsky N et al. (2009) The interaction of TIGIT with CD155 (PVR)and PVRL2 inhibits human NK cell cytotoxicity. Proc Natl Acad Sci U S A106:17858-17863.
10. Wu MR et al (2015) DNAM-1-based chimeric antigen receptors enhance T cell effector function and exhibit in vivo efficacy against melanoma. Cancer Immunol Immunother 64:409-418.
11. Xu Z et al. (2010) A novel interface consisting of homologous immunoglobulin superfamily members with multiple functions. Cell Mol Immunol 7:11-19.