Small-molecule PIK-93 modulates the tumor microenvironment to improve immune checkpoint blockade response
Menée à l'aide de lignées cellulaires et de xénogreffes sur des modèles murins, cette étude met en évidence l'intérêt thérapeutique de PIK-93, une petite molécule agissant sur la stabilité de PD-L1, pour améliorer la réponse des cellules cancéreuses aux inhibiteurs de point de contrôle immunitaire
Immune checkpoint inhibitors (ICIs) targeting PD-L1 immunotherapy are state-of-the-art treatments for advanced non–small cell lung cancer (NSCLC). However, the treatment response of certain patients with NSCLC is unsatisfactory because of an unfavorable tumor microenvironment (TME) and poor permeability of antibody-based ICIs. In this study, we aimed to discover small-molecule drugs that can modulate the TME to enhance ICI treatment efficacy in NSCLC in vitro and in vivo. We identified a PD-L1 protein-modulating small molecule, PIK-93, using a cell-based global protein stability (GPS) screening system. PIK-93 mediated PD-L1 ubiquitination by enhancing the PD-L1–Cullin-4A interaction. PIK-93 reduced PD-L1 levels on M1 macrophages and enhanced M1 antitumor cytotoxicity. Combined PIK-93 and anti–PD-L1 antibody treatment enhanced T cell activation, inhibited tumor growth, and increased tumor-infiltrating lymphocyte (TIL) recruitment in syngeneic and human peripheral blood mononuclear cell (PBMC) line–derived xenograft mouse models. PIK-93 facilitates a treatment-favorable TME when combined with anti–PD-L1 antibodies, thereby enhancing PD-1/PD-L1 blockade cancer immunotherapy. Small-molecule PIK-93 modulates PD-L1 stability though CUL4A and benefits the tumor microenvironment for immunotherapy.
Science Advances 2022