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

Rita C. Acúrcio, Sabina Pozzi, Barbara Carreira, Marta Pojo, Nuria Gómez-Cebrián, Sandra Casimiro, Adelaide Fernandes, Andreia Barateiro, Vitor Farricha, Joaquim Brito, Ana Paula Leandro, Jorge A.R. Salvador, Luís Graça, Leonor Puchades-Carrasco, Luís Costa, Ronit Satchi-Fainaro*, Rita C. Guedes*, Helena F. Florindo*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

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.

Original languageEnglish
Article numbere004695
JournalJournal for ImmunoTherapy of Cancer
Volume10
Issue number7
DOIs
StatePublished - 21 Jul 2022

Keywords

  • IMMUNOLOGY
  • Lymphocyte Activation
  • Lymphocytes, Tumor-Infiltrating
  • Programmed Cell Death 1 Receptor
  • Tumor Escape

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