PT  - JOURNAL ARTICLE
AU  - Preillon, Julie
AU  - Cuende, Julia
AU  - Rabolli, Virginie
AU  - Garnero, Lucile
AU  - Mercier, Marjorie
AU  - Wald, Noémie
AU  - Pappalardo, Angela
AU  - Denies, Sofie
AU  - Jamart, Diane
AU  - Michaux, Anne-Catherine
AU  - Pirson, Romain
AU  - Pitard, Vincent
AU  - Bagot, Martine
AU  - Prasad, Shruthi
AU  - Houthuys, Erica
AU  - Brouwer, Margreet
AU  - Marillier, Reece
AU  - Lambolez, Florence
AU  - Marchante, Joäo R.
AU  - Nyawouame, Florence
AU  - Carter, Mathew J.
AU  - Baron-Bodo, Véronique
AU  - Marie-Cardine, Anne
AU  - Cragg, Mark
AU  - Déchanet-Merville, Julie
AU  - Driessens, Gregory
AU  - Hoofd, Catherine
TI  - Restoration of T-cell Effector Function, Depletion of Tregs, and Direct Killing of Tumor Cells: The Multiple Mechanisms of Action of a-TIGIT Antagonist Antibodies
AID  - 10.1158/1535-7163.MCT-20-0464
DP  - 2021 Jan 01
TA  - Molecular Cancer Therapeutics
PG  - 121--131
VI  - 20
IP  - 1
4099  - http://mct.aacrjournals.org/content/20/1/121.short
4100  - http://mct.aacrjournals.org/content/20/1/121.full
SO  - Mol Cancer Ther2021 Jan 01; 20
AB  - TIGIT is an immune checkpoint inhibitor expressed by effector CD4+ and CD8+ T cells, NK cells, and regulatory T cells (Tregs). Inhibition of TIGIT-ligand binding using antagonistic anti-TIGIT mAbs has shown in vitro potential to restore T-cell function and therapeutic efficacy in murine tumor models when combined with an anti–PD(L)-1 antibody. In the current work, we demonstrate broader TIGIT expression than previously reported in healthy donors and patients with cancer with expression on γδ T cells, particularly in CMV-seropositive donors, and on tumor cells from hematologic malignancies. Quantification of TIGIT density revealed tumor-infiltrating Tregs as the population expressing the highest receptor density. Consequently, the therapeutic potential of anti-TIGIT mAbs might be wider than the previously described anti–PD(L)-1-like restoration of αβ T-cell function. CD155 also mediated inhibition of γδ T cells, an immune population not previously described to be sensitive to TIGIT inhibition, which could be fully prevented via use of an antagonistic anti-TIGIT mAb (EOS-448). In PBMCs from patients with cancer, as well as in tumor-infiltrating lymphocytes from mice, the higher TIGIT expression in Tregs correlated with strong antibody-dependent killing and preferential depletion of this highly immunosuppressive population. Accordingly, the ADCC/ADCP–enabling format of the anti-TIGIT mAb had superior antitumor activity, which was dependent upon Fcγ receptor engagement. In addition, the anti-TIGIT mAb was able to induce direct killing of TIGIT-expressing tumor cells both in human patient material and in animal models, providing strong rationale for therapeutic intervention in hematologic malignancies. These findings reveal multiple therapeutic opportunities for anti-TIGIT mAbs in cancer therapeutics.