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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

dc.rights.licenseopenen_US
dc.contributor.authorPREILLON, J.
dc.contributor.authorCUENDE, J.
dc.contributor.authorRABOLLI, V.
dc.contributor.authorGARNERO, L.
dc.contributor.authorMERCIER, M.
dc.contributor.authorWALD, N.
dc.contributor.authorDENIES, S.
dc.contributor.authorJAMART, D.
dc.contributor.authorMICHAUX, A.-C.
dc.contributor.authorPIRSON, R.
hal.structure.identifierImmunology from Concept and Experiments to Translation = Immunologie Conceptuelle, Expérimentale et Translationnelle [ImmunoConcept]
dc.contributor.authorPITARD, Vincent
dc.contributor.authorBAGOT, M.
dc.contributor.authorPRASAD, S.
dc.contributor.authorHOUTHUYS, E.
dc.contributor.authorBROUWER, M.
dc.contributor.authorMARILLIER, R.
dc.contributor.authorLAMBOLEZ, F.
dc.contributor.authorMARCHANTE, J.R.
dc.contributor.authorNYAWOUAME, F.
dc.contributor.authorCARTER, M.J.
dc.contributor.authorBARON-BODO, V.
dc.contributor.authorMARIE-CARDINE, A.
dc.contributor.authorCRAGG, M.
hal.structure.identifierImmunology from Concept and Experiments to Translation = Immunologie Conceptuelle, Expérimentale et Translationnelle [ImmunoConcept]
dc.contributor.authorDECHANET-MERVILLE, Julie
IDREF: 061667994
dc.contributor.authorDRIESSENS, G.
dc.contributor.authorHOOFD, C.
dc.date.accessioned2022-11-24T15:22:03Z
dc.date.available2022-11-24T15:22:03Z
dc.date.issued2021-01-05
dc.identifier.issn1538-8514 (online) 1535-7163 (print)en_US
dc.identifier.otherhttps://aacrjournals.org/mct/article/20/1/121/92971/Restoration-of-T-cell-Effector-Function-Depletionen_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/170386
dc.description.abstractEnTIGIT 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.
dc.language.isoENen_US
dc.title.enRestoration of t-cell effector function, depletion of tregs, and direct killing of tumor cells: The multiple mechanisms of action of a-tigit antagonist antibodies
dc.typeArticle de revueen_US
dc.identifier.doi10.1158/1535-7163.MCT-20-0464en_US
dc.subject.halSciences du Vivant [q-bio]/Immunologieen_US
dc.identifier.pubmed33277440en_US
bordeaux.journalMolecular Cancer Therapeuticsen_US
bordeaux.page121-131en_US
bordeaux.volume20en_US
bordeaux.hal.laboratoriesImmunoConcEpT - UMR 5164en_US
bordeaux.issue1en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionCNRSen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.exportfalse
dc.rights.ccPas de Licence CCen_US
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