Soft Synthetic Cells with Mobile Membrane Ligands for Ex Vivo Expansion of Therapy‐Relevant T Cell Phenotypes
Anna Burgstaller, Nils Piernitzki, Nadja Küchler, Marcus Koch, Thomas Kister, Hermann Eichler, Tobias Kraus, Eva C. Schwarz, Michael L. Dustin, Franziska Lautenschläger, Oskar Staufer
Abstract
Abstract The expansion of T cells ex vivo is crucial for effective immunotherapy but currently limited by a lack of expansion approaches that closely mimic in vivo T cell activation. Taking inspiration from bottom‐up synthetic biology, a new synthetic cell technology is introduced based on dispersed liquid‐liquid phase‐separated droplet‐supported lipid bilayers (dsLBs) with tunable biochemical and biophysical characteristics, as artificial antigen presenting cells (aAPCs) for ex vivo T cell expansion. These findings obtained with the dsLB technology reveal three key insights: first, introducing laterally mobile stimulatory ligands on soft aAPCs promotes expansion of IL‐4/IL‐10 secreting regulatory CD8 + T cells, with a PD‐1 negative phenotype, less prone to immune suppression. Second, it is demonstrated that lateral ligand mobility can mask differential T cell activation observed on substrates of varying stiffness. Third, dsLBs are applied to reveal a mechanosensitive component in bispecific Her2/CD3 T cell engager‐mediated T cell activation. Based on these three insights, lateral ligand mobility, alongside receptor‐ and mechanosignaling, is proposed to be considered as a third crucial dimension for the design of ex vivo T cell expansion technologies.