The PD-L1 interactome demonstrates bidirectional signaling coordinating immune suppression and cancer progression in HNSCC

Menée à l'aide de lignées cellulaires et de modèles murins de carcinome épidermoïde de la tête et du cou, cette étude met en évidence le rôle des domaines extracellulaires et intracellulaires de PD-L1 dans l'immunosuppression et la progression tumorale

Résumé en anglais

The programmed death receptor 1 (PD-1) and ligand (PD-L1) are validated cancer targets; however, emerging mechanisms and impact of PD-L1 intracellular signaling on cancer behavior are poorly understood. PD-L1 intracellular signaling increased clonogenicity, motility, and invasiveness in multiple head and neck squamous cell carcinoma (HNSCC) models, and PD-1 binding enhanced these effects. Protein: protein proximity labeling revealed the PD-L1 interactome, distinct for unbound and bound PD-1, which initiated cancer cell-intrinsic signaling. PD-L1 binding partners interleukin enhancer-binding factors 2 and 3 transduced their effect through STAT3. PD-L1 intracellular domain deletion (Δ260-290) disrupted signaling and reversed pro-growth properties. In humanized HNSCC in vivo models bearing T cells, PD-1 binding triggered PD-L1 signaling, and dual PD-L1 and STAT3 inhibition were required to achieve tumor control. Upon PD-1 binding, the PD-L1 extracellular and intracellular domains exert a synchronized effect to promote immune evasion by inhibiting T cell function while simultaneously enhancing cancer cell invasive properties.