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

Autor:	Acúrcio RC; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal., Pozzi S; Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel., Carreira B; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal., Pojo M; Unidade de Investigação em Patobiologia Molecular (UIPM) do Instituto Português de Oncologia de Lisboa Francisco Gentil EPE 1099-023, Lisbon, Portugal., Gómez-Cebrián N; Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain., Casimiro S; Instituto de Medicina Molecular - João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal., Fernandes A; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal., Barateiro A; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal., Farricha V; Serviço de Cirurgia do Instituto Português de Oncologia de Lisboa Francisco Gentil EPE, 1099-023 Lisbon, Portugal., Brito J; Serviço de Ortopedia, Centro Hospitalar Universitário Lisboa Norte, 1649-028 Lisbon, Portugal., Leandro AP; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal., Salvador JAR; Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra,Centre for Neuroscience and Cell Biology, 3000-548 Coimbra, Portugal., Graça L; Instituto de Medicina Molecular - João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal., Puchades-Carrasco L; Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain., Costa L; Instituto de Medicina Molecular - João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.; Serviço de Oncologia Médica, Centro Hospitalar Universitário Lisboa Norte, 1649-028, Lisbon, Portugal., Satchi-Fainaro R; Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel hflorindo@ff.ulisboa.pt rguedes@ff.ulisboa.pt ronitsf@tauex.tau.ac.il.; Sagol School of Neurosciences, Tel Aviv University, Tel Aviv 6997801, Israel., Guedes RC; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal hflorindo@ff.ulisboa.pt rguedes@ff.ulisboa.pt ronitsf@tauex.tau.ac.il., Florindo HF; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal hflorindo@ff.ulisboa.pt rguedes@ff.ulisboa.pt ronitsf@tauex.tau.ac.il.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2022 Jul; Vol. 10 (7).
DOI:	10.1136/jitc-2022-004695
Abstrakt:	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. Competing Interests: Competing interests: RS-F is a Board Director at Teva Pharmaceutical Industries. All other authors declare that they have no competing interests. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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