A yeast surface display platform for characterizing CAR T cell responses to cancer antigens

Marcus Deichmann, Giovanni Schiesaro, Keerthana Ramanathan, Katrine Zeeberg, Nanna M. T. Koefoed, Maria Ormhøj, Rasmus U. W. Friis, Ryan T. Gill, Sine R. Hadrup, Emil D. Jensen () and Michael K. Jensen ()
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Marcus Deichmann: Technical University of Denmark, Novo Nordisk Foundation Center for Biosustainability
Giovanni Schiesaro: Technical University of Denmark, Novo Nordisk Foundation Center for Biosustainability
Keerthana Ramanathan: Technical University of Denmark, Department of Health Technology
Katrine Zeeberg: Technical University of Denmark, Novo Nordisk Foundation Center for Biosustainability
Nanna M. T. Koefoed: Technical University of Denmark, Novo Nordisk Foundation Center for Biosustainability
Maria Ormhøj: Technical University of Denmark, Department of Health Technology
Rasmus U. W. Friis: Technical University of Denmark, Department of Health Technology
Ryan T. Gill: Technical University of Denmark, Novo Nordisk Foundation Center for Biosustainability
Sine R. Hadrup: Technical University of Denmark, Department of Health Technology
Emil D. Jensen: Technical University of Denmark, Novo Nordisk Foundation Center for Biosustainability
Michael K. Jensen: Technical University of Denmark, Novo Nordisk Foundation Center for Biosustainability

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Chimeric antigen receptor (CAR) T cells have become an established immunotherapy with promising results for the treatment of hematological malignancies. However, modulation of the targeted antigen’s surface level in cancer cells affects the quality and safety of CAR-T cell therapy. Here we present an engineered yeast-based antigen system for simulation of cancer cells with precise regulation of surface-antigen densities, providing a tool for controlled activation of CAR T cells and systematic assessment of antigen density effects. This Synthetic Cellular Advanced Signal Adapter (SCASA) system uses G protein-coupled receptor signaling to control cancer antigen densities on the yeast surface and provides a customizable platform allowing selectable signal inputs and modular pathway engineering for precise output fine-tuning. In relation to CD19+ cancers, we demonstrate synthetic cellular communication between CD19-displaying yeast and human CAR T cells as well as applications in high-throughput characterization of different CAR designs. We show that yeast is an alternative to conventional technologies (e.g. microbeads) and can provide higher activation control of clinically derived CAR T cells in vitro, relative to cancer cells. In summary, we present a customizable yeast-based platform for high-throughput characterization of CAR-T cell functionality and show potential applications within therapeutic T cells in clinical settings.

Date: 2025
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DOI: 10.1038/s41467-025-65236-7

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