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| Item Type: | Article |
|---|---|
| Title: | Selection of therapeutically effective T-cell receptors from the diverse tumor-bearing repertoire |
| Creators: |
Rosenberger, L., Hansmann, L.  ORCID: https://orcid.org/0000-0003-3790-0128, Anastasopoulou, V., Wolf, S.P. ORCID: https://orcid.org/0009-0008-2723-695X, Drousch, K., Moewes, C., Feng, X., Cao, G., Huang, J. ORCID: https://orcid.org/0000-0003-0271-4384, Yew, P.Y., Strønen, E. ORCID: https://orcid.org/0000-0001-9314-9389, Kato, T., Saligrama, N., Olweus, J., Nakamura, Y., Willimsky, G. ORCID: https://orcid.org/0000-0002-9693-948X, Blankenstein, T. ORCID: https://orcid.org/0000-0002-3357-4321, Schreiber, H. and Leisegang, M. ORCID: https://orcid.org/0000-0003-3692-7142
|
| 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-2K(b)-presented neoantigen p68(S551F) (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.Here, we mimic experimentally near-patient conditions to analyze the T-cell repertoire in euthymic tumor-bearing mice responding to the H-2K(b)-presented neoantigen p68(S551F) (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 CDK4(R24L). 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. |
| Keywords: | Adoptive Immunotherapy, Neoplasm Antigens, Neoplasms, T-Cell Antigen Receptors, T-Lymphocytes, Tumor Cell Line, Animals, Mice |
| Source: | Journal for ImmunoTherapy of Cancer |
| ISSN: | 2051-1426 |
| Publisher: | BMJ Publishing Group |
| Volume: | 13 |
| Number: | 5 |
| Page Range: | e011351 |
| Date: | 2 May 2025 |
| Official Publication: | https://doi.org/10.1136/jitc-2024-011351 |
| PubMed: | View item in PubMed |
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