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

Front Immunol. 2023 Feb 16:14:1119498. doi: 10.3389/fimmu.2023.1119498. eCollection 2023.

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: Rho (Rho GTPase); TCR gene therapy; humanized mouse models; melanoma; neoantigen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Membrane
  • DNA Repair
  • HLA-A Antigens
  • Humans
  • Melanoma*
  • Mice
  • Mice, Transgenic
  • Receptors, Antigen, T-Cell

Substances

  • Receptors, Antigen, T-Cell
  • HLA-A Antigens

Grants and funding

Funding was provided by grants from the German Research Foundation (SFB-TR36), the Berlin Institute of Health (CRG-1), Deutsche Krebshilfe (111546), DKTK joint funding (NEO-ATT), European Union (ERC Advanced Grant 882963) and the Helmholtz-Gemeinschaft, Zukunftsthema ‘Immunology and Inflammation’ (ZT-0027).