This project focuses on two aspects related to the molecular architecture and dynamics of immunological synapses (IS).
First, we will use state-of-the-art super-resolution fluorescence microscopy, including DNA-PAINT, to unravel the molecular architecture of immunological synapses (IS) at an unprecedented level of detail. The project will establish advanced labeling toolkits, incorporating nanobody- and single-chain variable fragment (scFv)-based probes, for precise targeting of proteins involved in IS formation, including T cell receptors (TCR), major histocompatibility complexes (MHC), co-stimulatory molecules (CD28, CD80), and inhibitory checkpoint regulators (PD-1, PD-L1). These probes will enable multiplexed imaging of molecular assemblies within the IS, elucidating interactions and nanoscale spatial arrangements critical to immune response modulation. Next, we will use DNA origami to arrange therapeutic agents
such as monoclonal antibodies, T cell bispecifics (TCBs), immune checkpoint modulators, and engineered chimeric antigen receptors (CARs) to influence the spatial organization and functional dynamics of key IS components. It will be a key question how the distribution of the imaged surface proteins correlates with the influence of the arrangements of the therapeutic agents on top of the DNA origami.
The approach aims at understanding the mechanistic impact of “patterned therapeutic” agents on IS organization, focusing on how changes in protein clustering, interaction affinities, and molecular dynamics influence immune cell activation or suppression. These insights will guide the rational design of next-generation immunotherapeutics with optimized efficacy and reduced off-target effects. Ultimately, this knowledge will enhance Roche’s capacity to model and design immune-modulatory drugs across oncology, autoimmunity, and inflammatory diseases.