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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

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
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
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.
1535-7163
121-131
Preillon, Julie
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Cuende, Julia
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Rabolli, Virginie
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Garnero, Lucile
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Mercier, Marjorie
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Wald, Noémie
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Pappalardo, Angela
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Denies, Sofie
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Jamart, Diane
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Michaux, Anne-catherine
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Pirson, Romain
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Pitard, Vincent
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Bagot, Martine
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Prasad, Shruthi
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Houthuys, Erica
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Brouwer, Margreet
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Marillier, Reece
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Lambolez, Florence
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Marchante, Joäo R.
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Nyawouame, Florence
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Carter, Mathew J.
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Baron-bodo, Véronique
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Marie-cardine, Anne
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Cragg, Mark
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Déchanet-merville, Julie
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Driessens, Gregory
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Hoofd, Catherine
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Preillon, Julie
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Cuende, Julia
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Rabolli, Virginie
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Garnero, Lucile
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Mercier, Marjorie
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Wald, Noémie
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Pappalardo, Angela
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Denies, Sofie
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Jamart, Diane
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Michaux, Anne-catherine
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Pirson, Romain
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Pitard, Vincent
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Bagot, Martine
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Prasad, Shruthi
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Houthuys, Erica
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Brouwer, Margreet
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Marillier, Reece
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Lambolez, Florence
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Marchante, Joäo R.
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Nyawouame, Florence
dc561437-4d74-4ddb-b2f7-90967400ed1a
Carter, Mathew J.
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Baron-bodo, Véronique
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Marie-cardine, Anne
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Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Déchanet-merville, Julie
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Driessens, Gregory
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Hoofd, Catherine
ef2782dd-5cab-4605-9448-80e12b6e7302

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).

Record type: Article

Abstract

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.

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Accepted/In Press date: 3 November 2020
e-pub ahead of print date: 4 December 2020
Published date: January 2021

Identifiers

Local EPrints ID: 447021
URI: http://eprints.soton.ac.uk/id/eprint/447021
ISSN: 1535-7163
PURE UUID: 48e31897-1bdb-4b15-8427-19729bd1cb16
ORCID for Mark Cragg: ORCID iD orcid.org/0000-0003-2077-089X

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Date deposited: 02 Mar 2021 17:30
Last modified: 22 Nov 2021 02:42

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Contributors

Author: Julie Preillon
Author: Julia Cuende
Author: Virginie Rabolli
Author: Lucile Garnero
Author: Marjorie Mercier
Author: Noémie Wald
Author: Angela Pappalardo
Author: Sofie Denies
Author: Diane Jamart
Author: Anne-catherine Michaux
Author: Romain Pirson
Author: Vincent Pitard
Author: Martine Bagot
Author: Shruthi Prasad
Author: Erica Houthuys
Author: Margreet Brouwer
Author: Reece Marillier
Author: Florence Lambolez
Author: Joäo R. Marchante
Author: Florence Nyawouame
Author: Mathew J. Carter
Author: Véronique Baron-bodo
Author: Anne Marie-cardine
Author: Mark Cragg ORCID iD
Author: Julie Déchanet-merville
Author: Gregory Driessens
Author: Catherine Hoofd

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