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Dual modulation of cytotoxic and checkpoint receptors tunes the efficacy of adoptive Delta One T cell therapy against colorectal cancer

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dc.contributor.authorBlanco Dominguez, Rafael
dc.contributor.authorBarros, Leandro
dc.contributor.authorCarreira, Mariana
dc.contributor.authorvan der Ploeg, Manon
dc.contributor.authorCondeço, Carolina
dc.contributor.authorMarsères, Gabriel
dc.contributor.authorFerreira, Cristina
dc.contributor.authorCosta, Carla
dc.contributor.authorFerreira, Carlos M.
dc.contributor.authorDéchanet-Merville, Julie
dc.contributor.authorde Miranda, Noel F. C. C.
dc.contributor.authorMensurado, Sofia
dc.contributor.authorSilva-Santos, Bruno
dc.date.accessioned2025-04-30T14:07:23Z
dc.date.available2025-04-30T14:07:23Z
dc.date.issued2025
dc.description© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/pt_PT
dc.description.abstractColorectal cancer (CRC) remains a challenge for current immunotherapies. Vδ1+ γδ T cells offer a promising alternative because of their HLA-I-independent cytotoxicity and natural tissue tropism. We developed Delta One T (DOT) cells, a Vδ1+ γδ T cell-based adoptive cell therapy clinically explored for hematological malignancies but not yet for solid tumors. Here we demonstrate the capacity of DOT cells to target CRC cell lines and patient-derived specimens and organoids in vitro and to control tumor growth in an orthotopic xenograft model of CRC. Notwithstanding, we found tumor-infiltrating DOT cells to exhibit a dysregulated balance of cytotoxic and inhibitory receptors that paralleled that of endogenous Vδ1+ tumor-infiltrating lymphocytes and limited their cytotoxicity. To maximize efficacy, we unveil two strategies, increasing targeting through upregulation of NKG2D ligands upon butyrate administration and blocking the checkpoints TIGIT and PD1, which synergistically unleashed DOT cell cytotoxicity. These findings support DOT cell-based combinatorial approaches for CRC treatment.pt_PT
dc.description.sponsorshipWe acknowledge funding from Takeda Development Center Americas (to B.S.-S., R.B.-D., L.B., M.C., S.M. and C.C.), EMBO Postdoctoral Fellowship (233-2023 to R.B.-D.), Fundação para a Ciência e Tecnologia (FCT), Ministério da Ciência, Tecnologia e Ensino Superior (PTDC/MED-ONC/6829/2020 to B.S.-S. and L.B.; 2021.01953.CEECIND to S.M.), Liga Portuguesa Contra o Cancro NRS (‘Dissecting the impact of the TME on DOT cells towards maximizing their therapeutic potential in CRC’ to R. B.-D., L.B., C.C. and S.M.) and Institut National contre le Cancer, Fondation ARC and LNCC (PAIR-2021-199 to J.D.-M.). We were also supported by iMM-CARE, funded by the European Union’s Horizon Europe research and innovation program under grant number 101060102 and cofunded by the Portuguese Government, the FCT, the Francisco Manuel dos Santos Society Group (ARICA, Investimentos, Participações e Gestão and Jerónimo Martins), the Gulbenkian Institute for Molecular Medicine and the Lisbon Academic Medical Center.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationNat Cancer. 2025 Apr 16.pt_PT
dc.identifier.doi10.1038/s43018-025-00948-9pt_PT
dc.identifier.eissn2662-1347
dc.identifier.urihttp://hdl.handle.net/10400.5/100369
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringer Naturept_PT
dc.relation101060102pt_PT
dc.relationRegulation of gamma-delta T cells in the tumor microenvironment and their manipulation towards immunotherapy of solid cancers
dc.relationDissecting regulators of anti-tumor gamma-delta T cells for improved solid cancer immunotherapy
dc.relation.publisherversionhttps://www.nature.com/natcancer/pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/pt_PT
dc.titleDual modulation of cytotoxic and checkpoint receptors tunes the efficacy of adoptive Delta One T cell therapy against colorectal cancerpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleRegulation of gamma-delta T cells in the tumor microenvironment and their manipulation towards immunotherapy of solid cancers
oaire.awardTitleDissecting regulators of anti-tumor gamma-delta T cells for improved solid cancer immunotherapy
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FMED-ONC%2F6829%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/CEEC IND4ed/2021.01953.CEECIND%2FCP1673%2FCT0007/PT
oaire.citation.titleNature Cancerpt_PT
oaire.fundingStream3599-PPCDT
oaire.fundingStreamCEEC IND4ed
person.familyNameBlanco Dominguez
person.familyNameBarros
person.familyNameCondeço
person.familyNameFerreira
person.familyNameMensurado Santos
person.familyNameSilva-Santos
person.givenNameRafael
person.givenNameLeandro
person.givenNameCarolina
person.givenNameCristina
person.givenNameSofia
person.givenNameBruno
person.identifierhttps://scholar.google.com/citations?user=83kKWFAAAAAJ&hl=en&oi=ao
person.identifier.ciencia-id0C10-CF71-1D15
person.identifier.ciencia-id7B1A-BC32-66FB
person.identifier.ciencia-idBA10-56F0-7CAD
person.identifier.ciencia-idD51E-6517-BE6A
person.identifier.orcid0000-0003-2448-8699
person.identifier.orcid0000-0002-7339-9994
person.identifier.orcid0000-0002-5046-4685
person.identifier.orcid0000-0001-6746-932X
person.identifier.orcid0000-0002-5157-0033
person.identifier.orcid0000-0003-4141-9302
person.identifier.scopus-author-id6505885924
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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