סמינר לפיזיקה של מערכות ביולוגיות וחומרים רכים: Nanoscale platforms for engineering of immunotherapeutic lymphocytes

Abstract:

Lymphocyte responses are regulated not only by biochemical signals but also by physical cues such as the spatial arrangement of signaling molecules, and the mechanics and topography of their environment. However, in-vivo, these cues are intertwined, making their individual roles difficult to distinguish. Ex vivo stimulation platforms overcome this by mimicking specific cues in a controlled manner. Recent nanotechnological advances now allow molecular-scale structuring of such cues, offering new opportunities to precisely regulate lymphocyte activation for immunotherapy.

In the first part of my talk, I’ll present platforms for studying physical cues in lymphocyte signaling. We first examined ligand arrangement in NK cells using platforms that controlled how segregation between activating and inhibitory ligands shapes signaling and cytotoxicity1. Varying segregation from 0–40 nm revealed inhibition dependence on spacing, supported by physical modeling. Follow-up work engineered platforms to control nanoscale clustering of activating and costimulatory ligands in T cells, showing clustering is crucial for activation at low ligand densities2,3. We also investigated elasticity and topography in T and NK cells using tunable vertical nanowires functionalized with antigens4, which provided mechanical and nano-topographical cues that enhanced immune  responses5–7.

In the second part, I’ll discuss applying these insights to CAR T cell therapy. We developed a mechano-topographical platform with elastic 3D micro-/nano-pillar arrays functionalized with activating and costimulatory antibodies. Systematic assessment of pillar geometry and elasticity showed effects on T cell activation, exhaustion, proliferation, and CAR transduction. Discriminant analysis identified optimal conditions that promoted memory CAR T cell differentiation. Integrating these surfaces into production protocols yielded CAR T cells with superior anti-tumor efficacy, validated in multiple models. Transcriptomic analysis confirmed stronger memory T cell signatures, representing a significant step forward in CAR T immunotherapy8.

To realize several of the platforms described above, we developed an innovative lithographic process based on the dry self-assembly of nanospheres, achieving exceptional precision and high packing density9,10. Beyond enabling scalable fabrication of T cell–stimulating nanostructures, this versatile process has also been applied to create advanced nanostructures for optical and self-cleaning applications.