Author(s):
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
Date: 2022
Persistent ID: http://hdl.handle.net/10451/54613
Origin: Repositório da Universidade de Lisboa
Subject(s): Immunology; Lymphocyte activation; Lymphocytes, tumor-infiltrating; Programmed cell death 1 receptor; Tumor escape
Description
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.
