Balancing the Nanoscale Organization in Multivalent Materials for Functional Inhibition of the Programmed Death‑1 Immune Checkpoint

• Published in: ACS nano 2024-01, Vol.18 (2), p.1381-1395
• Main Authors: Paloja, Kaltrina, Weiden, Jorieke, Hellmeier, Joschka, Eklund, Alexandra S., Reinhardt, Susanne C. M., Parish, Ian A., Jungmann, Ralf, Bastings, Maartje M. C.
• Format: Article
• Language: English
• Subjects: B7-H1 Antigen; DNA - metabolism; Humans; Neoplasms - metabolism; Programmed Cell Death 1 Receptor; T-Lymphocytes
• ISSN: 1936-0851; 1936-086X
• DOI: 10.1021/acsnano.3c06552

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.