Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironment
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2022 |
| Outros Autores: | , , , , , , , , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
| Texto Completo: | http://hdl.handle.net/10451/54613 |
Resumo: | © 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/. |
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Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironmentImmunologyLymphocyte activationLymphocytes, tumor-infiltratingProgrammed cell death 1 receptorTumor escape© 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/.Background: 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.C 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.BMJ Publishing GroupRepositório da Universidade de LisboaAcúrcio, Rita CPozzi, SabinaCarreira, BarbaraPojo, MartaGómez-Cebrián, NuriaCasimiro, SandraFernandes, AdelaideBarateiro, AndreiaFarricha, VitorSoares Do Brito, JoaquimLeandro, PSalvador, Jorge A. R.Graca, LuisPuchades-Carrasco, LeonorCosta, LuisSatchi-Fainaro, RonitGuedes, R. C.Florindo, Helena F2022-09-28T13:31:59Z20222022-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/54613engJ Immunother Cancer. 2022 Jul;10(7):e00469510.1136/jitc-2022-0046952051-1426info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T17:01:03Zoai:repositorio.ul.pt:10451/54613Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:05:24.035302Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
| dc.title.none.fl_str_mv |
Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironment |
| title |
Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironment |
| spellingShingle |
Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironment Acúrcio, Rita C Immunology Lymphocyte activation Lymphocytes, tumor-infiltrating Programmed cell death 1 receptor Tumor escape |
| title_short |
Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironment |
| title_full |
Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironment |
| title_fullStr |
Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironment |
| title_full_unstemmed |
Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironment |
| title_sort |
Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironment |
| author |
Acúrcio, Rita C |
| author_facet |
Acúrcio, Rita C Pozzi, Sabina Carreira, Barbara Pojo, Marta Gómez-Cebrián, Nuria Casimiro, Sandra Fernandes, Adelaide Barateiro, Andreia Farricha, Vitor Soares Do Brito, Joaquim Leandro, P Salvador, Jorge A. R. Graca, Luis Puchades-Carrasco, Leonor Costa, Luis Satchi-Fainaro, Ronit Guedes, R. C. Florindo, Helena F |
| author_role |
author |
| author2 |
Pozzi, Sabina Carreira, Barbara Pojo, Marta Gómez-Cebrián, Nuria Casimiro, Sandra Fernandes, Adelaide Barateiro, Andreia Farricha, Vitor Soares Do Brito, Joaquim Leandro, P Salvador, Jorge A. R. Graca, Luis Puchades-Carrasco, Leonor Costa, Luis Satchi-Fainaro, Ronit Guedes, R. C. Florindo, Helena F |
| author2_role |
author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Repositório da Universidade de Lisboa |
| dc.contributor.author.fl_str_mv |
Acúrcio, Rita C Pozzi, Sabina Carreira, Barbara Pojo, Marta Gómez-Cebrián, Nuria Casimiro, Sandra Fernandes, Adelaide Barateiro, Andreia Farricha, Vitor Soares Do Brito, Joaquim Leandro, P Salvador, Jorge A. R. Graca, Luis Puchades-Carrasco, Leonor Costa, Luis Satchi-Fainaro, Ronit Guedes, R. C. Florindo, Helena F |
| dc.subject.por.fl_str_mv |
Immunology Lymphocyte activation Lymphocytes, tumor-infiltrating Programmed cell death 1 receptor Tumor escape |
| topic |
Immunology Lymphocyte activation Lymphocytes, tumor-infiltrating Programmed cell death 1 receptor Tumor escape |
| 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/. |
| publishDate |
2022 |
| dc.date.none.fl_str_mv |
2022-09-28T13:31:59Z 2022 2022-01-01T00:00:00Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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publishedVersion |
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http://hdl.handle.net/10451/54613 |
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http://hdl.handle.net/10451/54613 |
| dc.language.iso.fl_str_mv |
eng |
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eng |
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J Immunother Cancer. 2022 Jul;10(7):e004695 10.1136/jitc-2022-004695 2051-1426 |
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BMJ Publishing Group |
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BMJ Publishing Group |
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