Balancing the Nanoscale Organization in Multivalent Materials for Functional Inhibition of the Programmed Death-1 Immune Checkpoint.
Kaltrina PalojaJorieke WeidenJoschka HellmeierAlexandra S EklundSusanne C M ReinhardtIan A ParishRalf JungmannMaartje M C BastingsPublished in: ACS nano (2023)
Dendritic cells (DCs) regulate immune priming by expressing programmed death ligand 1 (PD-L1) and PD-L2, which interact with the inhibitory receptor PD-1 on activated T cells. PD-1 signaling regulates T cell effector functions and limits autoimmunity. Tumor cells can hijack this pathway by overexpressing PD-L1 to suppress antitumor T cell responses. Blocking this inhibitory pathway has been beneficial for the treatment of various cancer types, although only a subset of patients responds. A deepened understanding of the spatial organization and molecular interplay between PD-1 and its ligands may inform the design of more efficacious nanotherapeutics. We visualized the natural molecular PD-L1 organization on DCs by DNA-PAINT microscopy and created a template to engineer DNA-based nanoclusters presenting PD-1 at defined valencies, distances, and patterns. These multivalent nanomaterials were examined for their cellular binding and blocking ability. Our data show that PD-1 nano-organization has profound effects on ligand interaction and that the valency of PD-1 molecules modulates the effectiveness in restoring T cell function. This work highlights the power of spatially controlled functional materials to unravel the importance of multivalent patterns in the PD-1 pathway and presents alternative design strategies for immune-engineering.
Keyphrases
- dendritic cells
- single molecule
- systematic review
- randomized controlled trial
- ejection fraction
- regulatory t cells
- circulating tumor
- newly diagnosed
- young adults
- papillary thyroid
- chronic kidney disease
- prognostic factors
- big data
- binding protein
- atomic force microscopy
- artificial intelligence
- patient reported
- high speed
- single cell
- transcription factor
- celiac disease
- lymph node metastasis
- smoking cessation
- label free
- type iii