TIGIT-CD226-PVR axis: advancing immune checkpoint blockade for cancer immunotherapy

Abstract

Recent advances in understanding the roles of immune checkpoints in allowing tumors to circumvent the immune system have led to successful therapeutic strategies that have fundamentally changed oncology practice. Thus far, immunotherapies against only two checkpoint targets have been approved, CTLA-4 and PD-L1/PD-1. Antibody blockade of these targets enhances the function of antitumor T cells at least in part by relieving inhibition of the T cell costimulatory receptor CD28. These successes have stimulated considerable interest in identifying other pathways that may bte targeted alone or together with existing immunotherapies. One such immune checkpoint axis is comprised of members of the PVR/nectin family that includes the inhibitory receptor T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory domains (TIGIT). Interestingly, TIGIT acts to regulate the activity of a second costimulatory receptor CD226 that works in parallel to CD28. There are currently over two dozen TIGIT-directed blocking antibodies in various phases of clinical development, testament to the promise of modulating this pathway to enhance antitumor immune responses. In this review, we discuss the role of TIGIT as a checkpoint inhibitor, its interplay with the activating counter-receptor CD226, and its status as the next advance in cancer immunotherapy.

Keywords: Costimulatory and Inhibitory T-Cell Receptors; Immunotherapy; Lymphocytes, Tumor-Infiltrating; Review.

Figure 1

The PVR/nectin family and receptor/ligand interactions. TIGIT, CD226, CD96, CD112R and KIR2DL5A are expressed on T cells and NK cells, whereas the ligands PVR, CD111, CD112, CD113 and PVRL4 are expressed on antigen-presenting cells (APCs) or frequently overexpressed on tumor cells. T cell immunoreceptor with Ig and ITIM domains (TIGIT) contains both immunoreceptor tyrosine-based inhibitory (ITIM) and immunoglobulin tyrosine tail (ITT)-like domains and has inhibitory (-) function in T cells and NK cells. CD112R and KIR2DL5A also contain ITIM domains and deliver inhibitory signals (−). CD96 contains an ITIM domain, but human CD96 also contains an YXXM motif. While CD96 has inhibitory function in NK cells, it may act as either an inhibitory (−) or activating (+) receptor in T cells. CD226 is an activating receptor (+), despite containing an ITT-like domain. interactions between ligands and receptors are denoted by arrows, with arrow thickness proportional to relative affinities. The strongest interactions are between TIGIT and PVR, and CD112R and CD112.

Figure 2

Mechanisms of T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibition of CD226. Left: CD28 and CD226 provide costimulatory signals to enable T cell activation on T cell receptor (TCR) engagement. Right: Following activation, inhibitory checkpoint receptors such as PD-1 and TIGIT are expressed by T cells, mediating suppression of activating signals. TIGIT and PD-1 disrupt CD226 and CD28 signaling through several mechanisms. (1) TIGIT has higher affinity than CD226 for shared ligands, allowing TIGIT to outcompete and displace CD226. (2) TIGIT disrupts CD226 homodimer formation, disabling capacity for CD226 activation. (3) Suppression of CD226 signaling by TIGIT and PD-1. CD226 phosphorylation is impaired or reduced in the presence of TIGIT extracellular domain or activated PD-1. Recruitment of Shp2 to activated PD-1 also impairs CD28 phosphorylation.

Figure 3

T cell immunoreceptor with Ig and ITIM domains (TIGIT) blockade may alleviate transcriptional programming mediated by Foxo1 in different immune cell populations. Left: TIGIT interferes with CD226 signaling, thereby inhibiting Akt phosphorylation and allowing Foxo1 to impair CD8⁺ T cell and NK cell function and enforce Treg suppressive function. Right: Blockade of TIGIT unleashes CD226 signaling, resulting in phosphorylation of Akt which subsequently phosphorylates Foxo1, leading to translocation of Foxo1 from the nucleus to the cytoplasm where Foxo1 is targeted for degradation. Reduction of Foxo1 transcriptional regulation may enhance CD8⁺ T cell and NK cell activity and impair suppressive activity of Tregs.

Figure 4

Anti-TIGIT monoclonal antibody therapies in clinical development. Molecule, clinical development phase, and Fc activity are indicated. Landscape as of November 2021. TIGIT, T cell immunoreceptor with Ig and ITIM domains.

Figure 5

Effects of dual blockade of T cell immunoreceptor with Ig and ITIM domains (TIGIT) and PD-(L)1 on antitumor immune responses. Left: Tumor-reactive CD8⁺ T cells encounter various immunosuppressive mechanisms (denoted by ‘-’) mediated by TIGIT and PD-1. In addition to inhibiting CD8⁺ T cells, TIGIT also inhibits NK cell activity. TIGIT signaling supports Treg suppressive function. Additionally, myeloid cells such as antigen-presenting cells contribute to a suppressive tumor microenvironment through release of cytokines such as IL-10 and TGF-β following PVR engagement of TIGIT. Tumor cells also express PVR and may contribute to immune suppression. Right: Anti-TIGIT combined with anti-PD-L1 reverses immunosuppression and modulates the tumor microenvironment to support antitumor responses (denoted by ‘+’). Dual blockade of TIGIT and PD-(L)1 allows costimulatory activation by CD28 and CD226 for fully competent CD8⁺ T cell effector activity. Release of CD226 from TIGIT restraint enhances NK cell activity. Treg suppression is impaired through blockade of TIGIT, and CD226 may promote a proinflammatory phenotype. Anti-TIGIT mAbs with an effector competent Fc capable of engaging Fcγ receptors (FcγR) allow additional mechanisms such as ADCC mediated by NK cells and ADCP mediated by macrophages that may lead to depletion of cells expressing high levels of TIGIT such as Tregs. In addition, Fc-FcγR interaction may modulate myeloid cells to relieve suppression and promote inflammatory conditions. The effects of CD226 engagement of PVR on tumor cells remains to be determined (denoted by ‘?’). NK, natural killer.