High-resolution profile of neoantigen-specific TCR activation links moderate stimulation to increased resilience of engineered TCR-T cells
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<sup>+</sup> 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.
Authors
- Dario Gosmann (ORCID: https://orcid.org/0000-0002-4973-4801)
- Niklas de Andrade Krätzig (ORCID: https://orcid.org/0000-0003-2141-6745)
- Sebastian Jarosch (ORCID: https://orcid.org/0000-0002-2908-8590)
- Franziska Füchsl (ORCID: https://orcid.org/0000-0001-5069-1442)
- Rupert Öllinger (ORCID: https://orcid.org/0000-0002-2292-5982)
- Piero Giansanti (ORCID: https://orcid.org/0000-0003-2857-0841)
- Carolin Vogelsang
- Michael Hiltensperger (ORCID: https://orcid.org/0000-0003-4600-1394)
- Eva Bräunlein (ORCID: https://orcid.org/0000-0001-9640-3741)
- Dirk Hans Busch (ORCID: https://orcid.org/0000-0001-8713-093X)
- Johannes Untch (ORCID: https://orcid.org/0000-0002-3193-8910)
- Eduardo Beltrán (ORCID: https://orcid.org/0000-0002-7266-4098)
- Angela M. Krackhardt (ORCID: https://orcid.org/0000-0002-4752-0543)
- Vladyslav Kavaka (ORCID: https://orcid.org/0009-0004-5837-3384)
- Roland Rad (ORCID: https://orcid.org/0000-0002-6849-9659)
- Gabriela Zuleger (ORCID: https://orcid.org/0009-0003-6771-3005)
- S. Braun (ORCID: https://orcid.org/0009-0009-9244-1033)
- Antonia Schwanzer
Institutions
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- TUM Klinikum (DE)
- Munich Cluster for Systems Neurology (DE)
- German Center for Infection Research (DE)
- Institute of Medical Microbiology and Hygiene (DE)
- Malteser-Krankenhaus (DE)
- Technical University of Munich (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-12-03
- DOI
- https://doi.org/10.1038/s41467-024-53911-0
- Citations
- 3
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 0.85
Funders
- Deutsche Forschungsgemeinschaft
- Else Kröner-Fresenius-Stiftung