Functional Anti-TIGIT Antibodies Regulate Development of Autoimmunity and Antitumor Immunity

Abstract

Coinhibitory receptors, such as CTLA-4 and PD-1, play a critical role in maintaining immune homeostasis by dampening T cell responses. Recently, they have gained attention as therapeutic targets in chronic disease settings where their dysregulated expression contributes to suppressed immune responses. The novel coinhibitory receptor TIGIT (T cell Ig and ITIM domain) has been shown to play an important role in modulating immune responses in the context of autoimmunity and cancer. However, the molecular mechanisms by which TIGIT modulates immune responses are still insufficiently understood. We have generated a panel of monoclonal anti-mouse TIGIT Abs that show functional properties in mice in vivo and can serve as important tools to study the underlying mechanisms of TIGIT function. We have identified agonistic as well as blocking anti-TIGIT Ab clones that are capable of modulating T cell responses in vivo. Administration of either agonist or blocking anti-TIGIT Abs modulated autoimmune disease severity whereas administration of blocking anti-TIGIT Abs synergized with anti-PD-1 Abs to affect partial or even complete tumor regression. The Abs presented in this study can thus serve as important tools for detailed analysis of TIGIT function in different disease settings and the knowledge gained will provide valuable insight for the development of novel therapeutic approaches targeting TIGIT.

TIGIT limits immune pathology during viral infections

“…Moreover, we found that early T cell activation was significantly reduced after agonistic TIGIT ligation in vivo, which correlated with the considerably reduced production of pro-inflammatory cytokines. This is in line with previous reports demonstrating the potential of TIGIT to attenuate T cell responses 9,15,31 .…”

“…1B), while the PD-1 expression on regulatory T cells remained unchanged over the course of chronic infection. The in vivo anti-TIGIT antibody (clone 1B4) was already shown to be non-depleting after immunization with MOG peptide 31 and we confirmed these findings in chronic LCMV infection ( Supplementary Fig. 1C).…”

“…A cardinal feature of exhausted T cells is the hierarchical and progressive loss of pro-inflammatory cytokine production, where IL-2 secretion is abolished prior to TNF secretion, and T cell exhaustion finally becomes terminal when the ability to produce IFN-γ is lost 2,33 . Conversely, we and others have previously shown that agonistic anti-TIGIT antibodies reduce proinflammatory cytokine production, both in vitro and in vivo 9,14,31 . We thus next analyzed whether TIGIT can modulate the expression of pro-inflammatory cytokines in T cells during both acute and chronic LCMV infection.…”

“…TIGIT modulates co-inhibitory receptors on CD8 + T cells. In order to determine the functional contribution of the TIGIT pathway toward promoting T cell exhaustion during chronic LCMV infection, we targeted TIGIT in vivo by using the blocking anti-TIGIT antibody (clone 1B4) we have generated and characterized previously 31 . Chronically infected C57BL/6 mice were continuously treated with either anti-TIGIT or mouse IgG1 control antibodies starting on the day of infection.…”

“…TIGIT correlates with IL-10 production in vivo. Given that IL-10 was shown to contribute to viral persistence in vivo 19,29,32 and that TIGIT signaling induces the production of IL-10 both directly and indirectly 11,31 , we speculated that TIGIT might hold a central role in contributing to viral persistence through its ability to induce IL-10. To further investigate this link between TIGIT and IL-10 expression in vivo, we chronically infected Thy1.1-IL-10 reporter with LCMV clone 13 and again treated NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-15025-1 ARTICLE them with blocking anti-TIGIT antibody (1B4) or isotype control.…”