Targeting the "PVR-TIGIT axis" with immune checkpoint therapies

Abstract

Checkpoint inhibitors have become an efficient way to treat cancers. Indeed, anti-CTLA-4, anti-PD1, and anti-PDL-1 antibodies are now used as therapies for cancers. However, while these therapies are very efficient in certain tumors, they remain poorly efficient in others. This might be explained by the immune infiltrate, the expression of target molecules, and the influence of the tumor microenvironment. It is therefore critical to identify checkpoint antigens that represent alternative targets for immunotherapies. PVR-like molecules play regulatory roles in immune cell functions. These proteins are expressed by different cell types and have been shown to be upregulated in various malignancies. PVR and Nectin-2 are expressed by tumor cells as well as myeloid cells, while TIGIT, CD96, and DNAM-1 are expressed on effector lymphoid cells. PVR is able to bind DNAM-1, CD96, and TIGIT, which results in two distinct profiles of effector cell activation. Indeed, while binding to DNAM-1 induces the release of cytokines and cytotoxicity of cytotoxic effector cells, binding TIGIT induces an immunosuppressive and non-cytotoxic profile. PVR is also able to bind CD96, which induces an immunosuppressive response in murine models. Unfortunately, in humans, results remain contradictory, and this interaction might induce the activation or the suppression of the immune response. Similarly, Nectin-2 was shown to bind TIGIT and to induce regulatory profiles in effectors cells such as NK and T cells. Therefore, these data highlight the potential of each of the molecules of the "PVR-TIGIT axis" as a potential target for immune checkpoint therapy. However, many questions remain to be answered to fully understand the mechanisms of this synapse, in particular for human CD96 and Nectin-2, which are still understudied. Here, we review the recent advances in "PVR-TIGIT axis" research and discuss the potential of targeting this axis by checkpoint immunotherapies.

Keywords: CD96; DNAM-1; Immune checkpoint therapy; Nectin2; PVR; TIGIT.

Figure 1.. The PVR–TIGIT axis.

PVR and Nectin-2 are expressed on APCs or tumor cells. TIGIT, CD96, and DNAM-1 are expressed on cytotoxic effector cells (CD8 ⁺ T cells and NK cells). PVR affinity for TIGIT is higher than its affinity for CD96 or DNAM-1. Thus, the signaling of the PVR–TIGIT synapse induces immunosuppression rather than effector cell activation and/or cytotoxicity. Signaling through PVR induces anti-inflammatory profiles in dendritic cells and macrophages. CD96 signaling induces immunosuppression in murine models, which was not demonstrated in human models. Similar to PVR, Nectin-2 binds PVR, CD96, or DNAM-1 but with a lower affinity than PVR. APC, antigen-presenting cell; DNAM-1, DNAX accessory molecule-1; NK, natural killer; PVR, poliovirus receptor; TIGIT, T Cell Immunoreceptor with Ig and ITIM domains.

Figure 2.. PVR’s role in immunomodulation.

A. Classical role of PVR in synapse signaling, tweaking the immune response toward a pro-tumoral profile. B. Using an antagonistic mAb directed against PVR would block its interaction with TIGIT, CD96, and DNAM-1. This would partially inhibit the signaling pathway, as the synapse would be maintained by Nectin-2 but with a much weaker affinity. Upon blockade, DNAM-1 expression would be upregulated in effector cells. APC, antigen-presenting cell; DNAM-1, DNAX accessory molecule-1; mAb, monoclonal antibody; NK, natural killer; PVR, poliovirus receptor; TIGIT, T Cell Immunoreceptor with Ig and ITIM domains.

Figure 3.. TIGIT immunosuppressive function.

TIGIT binds to its ligand, which induces the production of IL-10 and TGF-β by Tregs. This induces the polarization of T cells toward a Th2 profile, thus avoiding inflammation. IL-10 will create an anti-inflammatory microenvironment, which participates in the inhibition of CD8 ⁺ T cell cytotoxicity. The binding of TIGIT by its ligands induces a loss of cytotoxicity, immunosuppression, and exhaustion on effector cytotoxic cells. Signaling through TIGIT also blocks DNAM-1 dimerization, which leads to decreased DNAM-1 expression on effector cells. APC, antigen-presenting cell; DNAM-1, DNAX accessory molecule-1; IL, interleukin; PVR, poliovirus receptor; TGF, transforming growth factor; TIGIT, T Cell Immunoreceptor with Ig and ITIM domains; Th2, T helper type 2; Treg, regulatory T cell.

Figure 4.. Murine and human CD96 signaling and function in NK cells.

Murine CD96 possesses an intracellular ITIM motif, which leads to an inhibitory signal and the abrogation of the inflammatory immune response and cytotoxicity of NK cells. Human CD96 signaling is more complex and poorly studied. 1. The intracellular domain of human CD96 harbors a YXXM motif, which may or may not bind GRB2. GRB2 might lead to the activation or inhibition of NK cells. 2. Human CD96 signaling was shown to induce adhesion, migration, and cytotoxicity in NK cells. GRB2, growth factor receptor-bound protein 2; ITIM, immunoreceptor tyrosine-based inhibition motif; NK, natural killer.