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

Research output: Contribution to journalArticlepeer-review

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
JournalJournal for ImmunoTherapy of Cancer
Volume10
Issue number7
DOIs
StatePublished - 1 Jul 2022

Keywords

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

Fingerprint

Dive into the research topics of 'Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironment'. Together they form a unique fingerprint.

Cite this