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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.

Fecha de publicación:

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

  • Acurcio, Rita C.
  • Pozzi, Sabina
  • Carreira, Barbara
  • Pojo, Marta
  • Casimiro, Sandra
  • Fernandes, Adelaide
  • Barateiro, Andreia
  • Farricha, Vitor
  • Brito, Joaquim
  • Leandro, Ana Paula
  • Salvador, Jorge A. R.
  • Graca, Luis
  • Costa, Luis
  • Satchi-Fainaro, Ronit
  • Guedes, Rita C.
  • Florindo, Helena F.

Grupos

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.

© 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.

Datos de la publicación

ISSN/ISSNe:
2051-1426, 2051-1426

Journal for ImmunoTherapy of Cancer  BioMed Central

Tipo:
Article
Páginas:
-
PubMed:
35863821
Factor de Impacto:
3,450 SCImago ℠
Cuartil:
Q1 SCImago ℠

Citas Recibidas en Web of Science: 20

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Keywords

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

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HERRAMIENTAS DE RMN PARA EL DESARROLLO DE UNA PLATAFORMA PARA LA IDENTIFICACIÓN DE DIANAS, LA EVALUACIÓN DE FÁRMACOS Y LA PERSONALIZACIÓN DE TRATAMIENTOS BASADA EN APROXIMACIONES METABOLÓMICAS

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