High-resolution profile of neoantigen-specific TCR activation links moderate stimulation to increased resilience of engineered TCR-T cells

Franziska Füchsl, Johannes Untch, Vladyslav Kavaka, Gabriela Zuleger, Sarah Braun, Antonia Schwanzer, Sebastian Jarosch, Carolin Vogelsang, Niklas Andrade Krätzig, Dario Gosmann, Rupert Öllinger, Piero Giansanti, Michael Hiltensperger, Roland Rad, Dirk H. Busch, Eduardo Beltrán, Eva Bräunlein and Angela M. Krackhardt ()
Additional contact information
Franziska Füchsl: TUM University Hospital
Johannes Untch: TUM University Hospital
Vladyslav Kavaka: University Hospital
Gabriela Zuleger: TUM University Hospital
Sarah Braun: Institute for Medical Microbiology, Immunology and Hygiene
Antonia Schwanzer: TUM University Hospital
Sebastian Jarosch: Institute for Medical Microbiology, Immunology and Hygiene
Carolin Vogelsang: TUM University Hospital
Niklas Andrade Krätzig: TUM School of Medicine and Health
Dario Gosmann: TUM University Hospital
Rupert Öllinger: TUM School of Medicine and Health
Piero Giansanti: TUM School of Medicine and Health
Michael Hiltensperger: TUM University Hospital
Roland Rad: TUM School of Medicine and Health
Dirk H. Busch: Institute for Medical Microbiology, Immunology and Hygiene
Eduardo Beltrán: University Hospital
Eva Bräunlein: TUM University Hospital
Angela M. Krackhardt: TUM University Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Neoantigen-specific T cell receptors (neoTCRs) promise safe, personalized anti-tumor immunotherapy. However, detailed assessment of neoTCR-characteristics affecting therapeutic efficacy is mostly missing. Previously, we identified diverse neoTCRs restricted to different neoantigens in a melanoma patient. In this work, we now combine single-cell TCR-sequencing and RNA-sequencing after neoantigen-specific restimulation of peripheral blood-derived CD8+ T cells of this patient. We detect neoTCRs with specificity for the previously detected neoantigens and perform fine-characterization of neoTCR-transgenic (tg) T cells in vitro and in vivo. We describe a heterogeneous spectrum of TCR-intrinsic activation patterns in response to a shared neoepitope ranging from previously detected more highly frequent neoTCRs with moderate activation to rare ones with initially stronger activation. Experimental restimulation of adoptively transferred neoTCR-tg T cells in a xenogeneic rechallenge tumor model demonstrates superior anti-tumor responses of moderate neoTCR-tg T cells upon repeated tumor contact. These insights have significant implications for the selection of TCRs for therapeutic engineering of TCR-tg T cells.

Date: 2024
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DOI: 10.1038/s41467-024-53911-0

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