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Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironment

2022Journal article Open access
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dc.contributor.authorAcúrcio, Rita C
dc.contributor.authorPozzi, Sabina
dc.contributor.authorCarreira, Barbara
dc.contributor.authorPojo, Marta
dc.contributor.authorGómez-Cebrián, Nuria
dc.contributor.authorCasimiro, Sandra
dc.contributor.authorFernandes, Adelaide
dc.contributor.authorBarateiro, Andreia
dc.contributor.authorFarricha, Vitor
dc.contributor.authorSoares Do Brito, Joaquim
dc.contributor.authorLeandro, P
dc.contributor.authorSalvador, Jorge A. R.
dc.contributor.authorGraca, Luis
dc.contributor.authorPuchades-Carrasco, Leonor
dc.contributor.authorCosta, Luis
dc.contributor.authorSatchi-Fainaro, Ronit
dc.contributor.authorGuedes, R. C.
dc.contributor.authorFlorindo, Helena F
dc.date.accessioned2022-09-28T13:31:59Z
dc.date.available2022-09-28T13:31:59Z
dc.date.issued2022
dc.description© Author(s) (or their employer(s)) 2022.This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.pt_PT
dc.description.abstractBackground: Inhibiting programmed cell death protein 1 (PD-1) or PD-ligand 1 (PD-L1) has shown exciting clinical outcomes in diverse human cancers. So far, only monoclonal antibodies are approved as PD-1/PD-L1 inhibitors. While significant clinical outcomes are observed on patients who respond to these therapeutics, a large proportion of the patients do not benefit from the currently available immune checkpoint inhibitors, which strongly emphasize the importance of developing new immunotherapeutic agents. Methods: In this study, we followed a transdisciplinary approach to discover novel small molecules that can modulate PD-1/PD-L1 interaction. To that end, we employed in silico analyses combined with in vitro, ex vivo, and in vivo experimental studies to assess the ability of novel compounds to modulate PD-1/PD-L1 interaction and enhance T-cell function. Results: Accordingly, in this study we report the identification of novel small molecules, which like anti-PD-L1/PD-1 antibodies, can stimulate human adaptive immune responses. Unlike these biological compounds, our newly-identified small molecules enabled an extensive infiltration of T lymphocytes into three-dimensional solid tumor models, and the recruitment of cytotoxic T lymphocytes to the tumor microenvironment in vivo, unveiling a unique potential to transform cancer immunotherapy. Conclusions: We identified a new promising family of small-molecule candidates that regulate the PD-L1/PD-1 signaling pathway, promoting an extensive infiltration of effector CD8 T cells to the tumor microenvironment.pt_PT
dc.description.sponsorshipC and RCA are supported by the Fundação para a Ciência e a Tecnologia, Ministério da Ciência, Tecnologia e Ensino Superior (FCT-MCTES) (PhD grants PD/BD/128238/2016 (RCA) and SFRH/BD/131969/2017 (BC)). The authors thank the funding received from the European Structural & Investment Funds through the COMPETE Programme and from National Funds through FCT under the Programme grant LISBOA-01-0145-FEDER016405 - SAICTPAC/0019/2015 (HF and RCG). HFF and RCA received additional support from FCT-MCTES (UIDB/04138/2020, PTDC/BTM-SAL/4350/2021 and UTAPEXPL/NPN/0041/2021; EXPL/MED-QUI/1316/2021, respectively). The MultiNano@MBM project was supported by The Israeli Ministry of Health, and FCTMCTES, under the frame of EuroNanoMed-II (ENMed/0051/2016; HF and RS-F). HF and RS-F thank the generous financial support from ‘La Caixa’ Foundation under the framework of the Healthcare Research call 2019 (NanoPanther; LCF/PR/HR19/52160021), as well as CaixaImpulse (Co-Vax; LCF/TR/CD20/52700005). MP thanks the financial support from Liga Portuguesa Contra o Cancro – Nucleo Regional do Sul and ‘iNOVA4Health – UIDB/04462/2020’, a program financially supported by Fundação para a Ciência e Tecnologia/Ministério da Educação e Ciência. RS-F thanks the following funding agencies for their generous support: the European Research Council (ERC) Advanced Grant Agreement No. (835227)–3DBrainStrom, ERC PoC Grant Agreement no. 862580 – 3DCanPredict, The Israel Science Foundation (Grant No. 1969/18), The Melanoma Research Alliance (MRA Established Investigator Award n°615808), the Israel Cancer Research Fund (ICRF) Professorship award (n° PROF-18-682), and the Morris Kahn Foundation.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationJ Immunother Cancer. 2022 Jul;10(7):e004695pt_PT
dc.identifier.doi10.1136/jitc-2022-004695pt_PT
dc.identifier.eissn2051-1426
dc.identifier.urihttp://hdl.handle.net/10451/54613
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherBMJ Publishing Grouppt_PT
dc.relationLISBOA-01-0145-FEDER016405pt_PT
dc.relationDiscovery and development of novel small molecule immune system modulators
dc.relationPrecision nanotechnology-based therapeutic approaches to enhance tumor-immune cells crosstalk within melanoma stromal microenvironment
dc.relationPRECISION ONCOLOGY BY INNOVATIVE THERAPIES AND TECHNOLOGIES
dc.relationResearch Institute for Medicines
dc.relationMultifunctional nano-immunotherapy for melanoma brain metastases treatment
dc.relationNew opportunities for small molecules in immuno-oncology
dc.relationiNOVA4Health - Programme in Translational Medicine (iBET, CEDOC/FCM, IPOLFG e ITQB)
dc.relationBrain metastases: Deciphering tumor-stroma interactions in three dimensions for the rational design of nanomedicines
dc.relationPredicting clinical response to anticancer drugs using 3D-bioprinted tumor models for personalized therapy
dc.relation.publisherversionhttps://jitc.bmj.com/pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/pt_PT
dc.subjectImmunologypt_PT
dc.subjectLymphocyte activationpt_PT
dc.subjectLymphocytes, tumor-infiltratingpt_PT
dc.subjectProgrammed cell death 1 receptorpt_PT
dc.subjectTumor escapept_PT
dc.titleTherapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironmentpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleDiscovery and development of novel small molecule immune system modulators
oaire.awardTitlePrecision nanotechnology-based therapeutic approaches to enhance tumor-immune cells crosstalk within melanoma stromal microenvironment
oaire.awardTitlePRECISION ONCOLOGY BY INNOVATIVE THERAPIES AND TECHNOLOGIES
oaire.awardTitleResearch Institute for Medicines
oaire.awardTitleMultifunctional nano-immunotherapy for melanoma brain metastases treatment
oaire.awardTitleNew opportunities for small molecules in immuno-oncology
oaire.awardTitleiNOVA4Health - Programme in Translational Medicine (iBET, CEDOC/FCM, IPOLFG e ITQB)
oaire.awardTitleBrain metastases: Deciphering tumor-stroma interactions in three dimensions for the rational design of nanomedicines
oaire.awardTitlePredicting clinical response to anticancer drugs using 3D-bioprinted tumor models for personalized therapy
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//PD%2FBD%2F128238%2F2016/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F131969%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/9471 - RIDTI/SAICTPAC%2F0019%2F2015/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04138%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FBTM-SAL%2F4350%2F2021/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/EXPL%2FMED-QUI%2F1316%2F2021/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04462%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/835227/EU
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/862580/EU
oaire.citation.issue7pt_PT
oaire.citation.titleJournal for ImmunoTherapy of Cancerpt_PT
oaire.citation.volume10pt_PT
oaire.fundingStream9471 - RIDTI
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person.givenNameJORGE A. R.
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