Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironment. Issue 7 (21st July 2022)

• Record Type: Journal Article
• Authors: Acúrcio, Rita C.; Pozzi, Sabina; Carreira, Barbara; Pojo, Marta; Gómez-Cebrián, Nuria; Casimiro, Sandra; Fernandes, Adelaide; Barateiro, Andreia; Farricha, Vitor; Brito, Joaquim; Leandro, Ana Paula; Salvador, Jorge A R; Graça, Luís; Puchades-Carrasco, Leonor; Costa, Luís; Satchi-Fainaro, Ronit; Guedes, Rita C.; Florindo, Helena F.
• Is Part Of: Journal for immunotherapy of cancer. Volume 10:Issue 7(2022)
• Publication Date: 2022-07-21
• Subjects: IMMUNOLOGY -- Tumor Escape -- Lymphocytes, Tumor-Infiltrating -- Lymphocyte Activation -- Programmed Cell Death 1 Receptor; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2022-004695
• Languages: English
• ISSNs: 2051-1426

Abstract

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.