Preillon, Julie, Cuende, Julia, Rabolli, Virginie, Garnero, Lucile, Mercier, Marjorie, Wald, Noémie, Pappalardo, Angela, Denies, Sofie, Jamart, Diane, Michaux, Anne-catherine, Pirson, Romain, Pitard, Vincent, Bagot, Martine, Prasad, Shruthi, Houthuys, Erica, Brouwer, Margreet, Marillier, Reece, Lambolez, Florence, Marchante, Joäo R., Nyawouame, Florence, Carter, Mathew J., Baron-bodo, Véronique, Marie-cardine, Anne, Cragg, Mark, Déchanet-merville, Julie, Driessens, Gregory and Hoofd, Catherine (2021) 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. Molecular Cancer Therapeutics, 20 (1), 121-131. (doi:10.1158/1535-7163.MCT-20-0464).
Abstract
TIGIT is an immune checkpoint inhibitor expressed by effector CD4 þ and CD8 þ 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 gd 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 ab T-cell function. CD155 also mediated inhibition of gd 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 Fcg 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.
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