Targeting the recurrent Rac1P29S neoepitope in melanoma with heterologous high-affinity T cell receptors

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.

Automated summary

Here, we isolated and characterized TCRs specific to the neoepitope FSGEYIPTV, which is a common hotspot mutation in melanoma. TCR-transduced T cells targeting Rac1P29S demonstrated cytotoxicity against melanoma cells expressing this mutation, leading to tumor regression in vivo. Additionally, we found that a TCR raised against a heterologous mutation (Rac2P29L) more efficiently targeted the common melanoma mutation Rac1P29S. Our study highlights the therapeutic potential of Rac1P29S-specific TCR-transduced T cells and reveals a novel strategy of using heterologous peptides to generate more efficient TCRs.