Targeting the recurrent Rac1P29S neoepitope in melanoma with heterologous high-affinity T cell receptors
Authors
- L. Immisch
- G. Papafotiou
- N. Gallarín Delgado
- V. Scheuplein
- A. Paschen
- T. Blankenstein
- G. Willimsky
Journal
- Frontiers in Immunology
Citation
- Front Immunol 14: 1119498
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.