Building an immunological synapse with bispecific engagers

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Abstract:
The immunological synapses (IS) is the specialized contact between a T cell and antigen presenting cell that serves effector function for helper and cytotoxic T cells. A key feature of the IS is the transport of TCR microclusters to the centre, where signaling is terminated. We discovered using correlative light and electron microscopy that TCR were ectocytosed in the centre of the synapse. These vesicles also serve as an antigen specific carrier for CD40-ligand, a critical signal delivered by helper T cells¹. We next adapted our technology to investigate how CD8 cytotoxic T cells (CTL) and NK cells use nanoscale protein “bombs” with a core of cytotoxic perforin and granzymes and a shell of thrombospondin-1 (TSP-1) that are secreted into the synaptic cleft to kill target cells². We have referred to these “bombs” as supramolecular attack particles (SMAPs).

T cell engagers (TcE) are an important drug class with several recent drug approvals. Oskar Staufer and Alex Leithner developed a pipeline to deconvolve the features of TcE with an IgG Fc core³. They found that adhesion, CD45 exclusion and CD2-CD58 recruitment are parameters contributing to the potency range of a basic panel of TcE that differ in paratope spacing (distance between the tumour antigen and T cell receptor engaging arms).

Another way to use engagers is to enhance link two proteins on the same cell. An examples of this Cue Biopharma’s ImmunoSTAT, biologic linking a specific TCR ligand to an attenuated form of IL-2, leading to “personalized” cytokine delivery for T cells⁴. Study of the mechanism of these drugs has revealed a close working relationship between the TCR and IL-2 receptor.

While T cells form an efficient synapse with a sustained adhesion ring with mobile ICAM-1 and TCR ligands⁵, studies on dendritic cells suggest that restriction of ICAM- 1 mobility increases T cell activation⁶. Leithner has recently developed a new method to selectively control the lateral mobility of one component in a synthetic bilayer at a time, which has provided further evidence that control of ICAM-1 mobility is important for T cell activation through integrin costimulation.

1 Cespedes, P. F. et al. T-cell trans-synaptic vesicles are distinct and carry greater effector content than constitutive extracellular vesicles. Nat Commun 13, 3460 (2022). https://doi.org:10.1038/s41467-022-31160-3
2 Balint, S. et al. Supramolecular attack particles are autonomous killing entities released from cytotoxic T cells. Science 368, 897-901 (2020). https://doi.org:10.1126/science.aay9207
3 Staufer, O. et al. Solution structure and synaptic analyses reveal molecular mechanisms of bispecific T cell engagers. bioRxiv, 2022.2006.2015.496334 (2023). https://doi.org:10.1101/2022.06.15.496334
4 Seidel, R. D. et al. Peptide-HLA-based immunotherapeutics platforms for direct modulation of antigen-specific T cells. Sci Rep 11, 19220 (2021). https://doi.org:10.1038/s41598-021-98716-z
5 Grakoui, A. et al. The immunological synapse: a molecular machine controlling T cell activation. Science 285, 221-227 (1999).
6 Comrie, W. A., Li, S., Boyle, S. & Burkhardt, J. K. The dendritic cell cytoskeleton promotes T cell adhesion and activation by constraining ICAM-1 mobility. J Cell Biol 208, 457-473 (2015). https://doi.org:10.1083/jcb.201406120