Abstract 3249: a-TIGIT mediates antitumor activity through multiple mechanisms of action involving activation of intratumor effector T cells and depletion of regulatory T cells

T cell Immunoreceptor with Ig and ITIM domains (TIGIT) is a co-inhibitory receptor expressed by lymphocytes, preferentially CD8+ T cells, NK, as well as regulatory T cells (Treg). TIGIT can be bound by several ligands including CD155 and CD112 that are frequently expressed by tumor cells. In cancer, TIGIT expression is upregulated on conventional T cells and even more on regulatory T cells. Co-expression with exhaustion markers such as PD-1 is common, giving a strong rationale for blocking TIGIT as a therapeutic approach for reversing T or NK cell dysfunction linked with cancer progression. The mechanism of action of novel a-TIGIT monoclonal antibody (mAb) was characterized in vivo in the murine CT26 tumor model. This model mimics the human situation based on expression of TIGIT ligands on tumor cells and infiltration by effector and regulatory T cells that express higher levels of TIGIT compared to splenocytes. Two different isotypes (mIgG2a and mIgG1) of a-TIGIT mAb were used to evaluate anti-tumor efficacy, with only the mIgG2a, deleting isotype able to induce strong antitumor efficacy. The importance of Fc gamma receptors (FcγR) for the antitumor efficacy of a-TIGIT activity was further demonstrated by the use of mice KO for activatory FcγR or by depletion of NK cells which also resulted in the loss of a-TIGIT activity. The anti-tumor efficacy of a-TIGIT mAb was associated with an increased activity of conventional CD8+ and CD4+ T cells but also with a preferential depletion of Treg within the tumor microenvironment. This activity also correlated with full occupancy of TIGIT receptor in mice. As it has been shown that TIGIT is expressed on tumor cells in certain hematological cancers, we also established a model of EL4 tumor with engineered TIGIT expression. In this model, a-TIGIT demonstrates a strong antitumor effect that strictly depends on the isotype of the mAb. Finally, the activity of a-TIGIT was tested in less immunogenic models including of pancreatic PancO2 cancer where it demonstrated some tumor growth delay as a single agent and very strong combination potential with other immune checkpoints. In summary, these results show that antitumor mediated efficacy of a-TIGIT mAb depends upon target binding and also on interaction with FcγR. These findings support the clinical evaluation of a-TIGIT mAb able to engage those receptors. Citation Format: Julie Preillon, Sofie Denies, Diane Jamart, Matthew J. Carter, Mark S. Cragg, Gregory Driessens. a-TI