Targeting the recurrent Rac1P29S neoepitope in melanoma with heterologous high-affinity T cell receptors
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Published:2023-02-16
Issue:
Volume:14
Page:
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ISSN:1664-3224
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Container-title:Frontiers in Immunology
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language:
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Short-container-title:Front. Immunol.
Author:
Immisch Lena,Papafotiou George,Gallarín Delgado Nerea,Scheuplein Vivian,Paschen Annette,Blankenstein Thomas,Willimsky Gerald
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.
Funder
Deutsche Forschungsgemeinschaft
Deutsche Krebshilfe
Berlin Institute of Health
Deutschen Konsortium für Translationale Krebsforschung
European Commission
Helmholtz-Gemeinschaft
Publisher
Frontiers Media SA
Subject
Immunology,Immunology and Allergy
Cited by
1 articles.
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