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| Item Type: | Article |
|---|---|
| Title: | Targeting the recurrent Rac1P29S neoepitope in melanoma with heterologous high-affinity T cell receptors |
| Creators Name: | Immisch, L. and Papafotiou, G. and Gallarín Delgado, N. and Scheuplein, V. and Paschen, A. and Blankenstein, T. and Willimsky, G. |
| Abstract: | Recurrent neoepitopes are cancer-specific antigens common among groups of patients and therefore ideal targets for adoptive T cell therapy. The neoepitope FSGEYIPTV carries the Rac1P29S amino acid change caused by a c.85C>T missense mutation, which is the third most common hotspot mutation in melanoma. Here, we isolated and characterized TCRs to target this HLA- A*02:01-binding neoepitope by adoptive T cell therapy. Peptide immunization elicited immune responses in transgenic mice expressing a diverse human TCR repertoire restricted to HLA-A*02:01, which enabled isolation of high-affinity TCRs. TCR-transduced T cells induced cytotoxicity against Rac1P29S expressing melanoma cells and we observed regression of Rac1P29S expressing tumors in vivo after adoptive T cell therapy (ATT). Here we found that a TCR raised against a heterologous mutation with higher peptide-MHC affinity (Rac2P29L) more efficiently targeted the common melanoma mutation Rac1P29S. Overall, our study provides evidence for the therapeutic potential of Rac1P29S-specific TCR- transduced T cells and reveal a novel strategy by generating more efficient TCRs by heterologous peptides. |
| Keywords: | Neoantigen, TCR Gene Therapy, Melanoma, Rho (Rho GTPase), Humanized Mouse Models, Animals, Mice |
| Source: | Frontiers in Immunology |
| ISSN: | 1664-3224 |
| Publisher: | Frontiers Media SA |
| Volume: | 14 |
| Page Range: | 1119498 |
| Date: | 16 February 2023 |
| Official Publication: | https://doi.org/10.3389/fimmu.2023.1119498 |
| PubMed: | View item in PubMed |
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