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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 mel...

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Autores principales: Immisch, Lena, Papafotiou, George, Gallarín Delgado, Nerea, Scheuplein, Vivian, Paschen, Annette, Blankenstein, Thomas, Willimsky, Gerald
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9978334/
https://www.ncbi.nlm.nih.gov/pubmed/36875127
http://dx.doi.org/10.3389/fimmu.2023.1119498
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author Immisch, Lena
Papafotiou, George
Gallarín Delgado, Nerea
Scheuplein, Vivian
Paschen, Annette
Blankenstein, Thomas
Willimsky, Gerald
author_facet Immisch, Lena
Papafotiou, George
Gallarín Delgado, Nerea
Scheuplein, Vivian
Paschen, Annette
Blankenstein, Thomas
Willimsky, Gerald
author_sort Immisch, Lena
collection PubMed
description 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.
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spelling pubmed-99783342023-03-03 Targeting the recurrent Rac1P29S neoepitope in melanoma with heterologous high-affinity T cell receptors Immisch, Lena Papafotiou, George Gallarín Delgado, Nerea Scheuplein, Vivian Paschen, Annette Blankenstein, Thomas Willimsky, Gerald Front Immunol Immunology 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. Frontiers Media S.A. 2023-02-16 /pmc/articles/PMC9978334/ /pubmed/36875127 http://dx.doi.org/10.3389/fimmu.2023.1119498 Text en Copyright © 2023 Immisch, Papafotiou, Gallarín Delgado, Scheuplein, Paschen, Blankenstein and Willimsky https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Immisch, Lena
Papafotiou, George
Gallarín Delgado, Nerea
Scheuplein, Vivian
Paschen, Annette
Blankenstein, Thomas
Willimsky, Gerald
Targeting the recurrent Rac1P29S neoepitope in melanoma with heterologous high-affinity T cell receptors
title Targeting the recurrent Rac1P29S neoepitope in melanoma with heterologous high-affinity T cell receptors
title_full Targeting the recurrent Rac1P29S neoepitope in melanoma with heterologous high-affinity T cell receptors
title_fullStr Targeting the recurrent Rac1P29S neoepitope in melanoma with heterologous high-affinity T cell receptors
title_full_unstemmed Targeting the recurrent Rac1P29S neoepitope in melanoma with heterologous high-affinity T cell receptors
title_short Targeting the recurrent Rac1P29S neoepitope in melanoma with heterologous high-affinity T cell receptors
title_sort targeting the recurrent rac1p29s neoepitope in melanoma with heterologous high-affinity t cell receptors
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9978334/
https://www.ncbi.nlm.nih.gov/pubmed/36875127
http://dx.doi.org/10.3389/fimmu.2023.1119498
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