Balancing the Nanoscale Organization in Multivalent Materials for Functional Inhibition of the Programmed Death-1 Immune Checkpoint
- Author(s)
- Paloja, K; Weiden, J; Hellmeier, J; Eklund, AS; Reinhardt, SCM; Parish, IA; Jungmann, R; Bastings, MMC;
- Details
- Publication Year 2024-12-21,Volume 18,Issue #2,Page 1381-1395
- Journal Title
- ACS Nano
- Publication Type
- Research article
- Abstract
- 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.
- Keywords
- DNA origami; Pd-1; T cell activation; dendritic cells; immune checkpoint blockade; multivalency; spatial organization
- Department(s)
- Laboratory Research
- Publisher's Version
- https://doi.org/10.1021/acsnano.3c06552
- Open Access at Publisher's Site
https://doi.org/10.1021/acsnano.3c06552- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2024-01-19 06:43:10
Last Modified: 2024-01-19 06:48:25