Therapeutic Targeting of PD-1/PD-L1 Blockade by Novel Small-molecule Inhibitors Recruits Cytotoxic T Cells into Solid Tumor Microenvironment

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 analyses combined with , , and 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 , 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.