Rosenberger, Leonie and Hansmann, Leo and Anastasopoulou, Vasiliki and Wolf, Steven P. and Drousch, Kimberley and Moewes, Christina and Feng, Xinyi and Cao, Guoshuai and Huang, Jun and Yew, Poh Yin and Stronen, Erlend and Kato, Taigo and Saligrama, Naresha and Olweus, Johanna and Nakamura, Yusuke and Willimsky, Gerald and Blankenstein, Thomas and Schreiber, Hans and Leisegang, Matthias (2025) Selection of therapeutically effective T-cell receptors from the diverse tumor-bearing repertoire. JOURNAL FOR IMMUNOTHERAPY OF CANCER, 13 (5): e011351. ISSN , 2051-1426
Full text not available from this repository. (Request a copy)Abstract
Background The development of T-cell receptor (TCR)-based T-cell therapies is hampered by the difficulties in identifying therapeutically effective tumor-specific TCRs from the natural repertoire of a patient's cancer-specific T cells.Methods Here, we mimic experimentally near-patient conditions to analyze the T-cell repertoire in euthymic tumor-bearing mice responding to the H-2Kb-presented neoantigen p68S551F (mp68). We temporarily separated the time point of mp68 expression from that of cancer cell transplantation to exclude the influence of injection-induced inflammation on T-cell priming. Thus, the mp68-specific T-cell response could only develop after the acute inflammatory phase had subsided.Results We found that mp68-specific TCRs isolated from either tumor-infiltrating T cells or spleens of mice immunized with mp68-expressing cancer cells are diverse and not inherently therapeutic when introduced into peripheral T cells and used for adoptive therapy of established tumors. While measuring short-term T-cell responses in vitro was unreliable for some TCRs in predicting their therapeutic failure, assessing the persistence of cancer cell destruction by TCR-modified T cells in long-term cultures accurately predicted therapeutic outcomes. A tumor-derived TCR with optimal function was also correctly identified with this approach when analyzing human TCRs that recognize the HLA-A2-presented neoantigen CDK4R24L.Conclusions We show that a neoantigen-directed T-cell response in tumor-bearing hosts comprises a diverse repertoire. Infiltration and expansion of certain T-cell clonotypes in the tumor do not necessarily correlate with therapeutic efficacy of their TCRs in adoptive therapy. We propose that analysis of persistent rather than immediate responses of TCR-modified T cells in vitro serves as a reliable parameter to identify TCRs that are therapeutically effective in vivo.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ANTIGEN; LYMPHOCYTES; NEOANTIGENS; EFFICIENT; VECTORS; MICE; TCR; T cell Receptor - TCR; Tumor infiltrating lymphocyte - TIL; T cell; Adoptive cell therapy - ACT; Immunotherapy |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 31 Mar 2026 08:22 |
| Last Modified: | 31 Mar 2026 08:22 |
| URI: | https://pred.uni-regensburg.de/id/eprint/67869 |
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