In vitro proteasome processing of neo-splicetopes does not predict their presentation in vivo.
Elife
; 102021 04 20.
Article
em En
| MEDLINE
| ID: mdl-33875134
ABSTRACT
Proteasome-catalyzed peptide splicing (PCPS) of cancer-driving antigens could generate attractive neoepitopes to be targeted by T cell receptor (TCR)-based adoptive T cell therapy. Based on a spliced peptide prediction algorithm, TCRs were generated against putative KRASG12V- and RAC2P29L-derived neo-splicetopes with high HLA-A*0201 binding affinity. TCRs generated in mice with a diverse human TCR repertoire specifically recognized the respective target peptides with high efficacy. However, we failed to detect any neo-splicetope-specific T cell response when testing the in vivo neo-splicetope generation and obtained no experimental evidence that the putative KRASG12V- and RAC2P29L-derived neo-splicetopes were naturally processed and presented. Furthermore, only the putative RAC2P29L-derived neo-splicetopes was generated by in vitro PCPS. The experiments pose severe questions on the notion that available algorithms or the in vitro PCPS reaction reliably simulate in vivo splicing and argue against the general applicability of an algorithm-driven 'reverse immunology' pipeline for the identification of cancer-specific neo-splicetopes.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptores de Antígenos de Linfócitos T
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Processamento de Proteína Pós-Traducional
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Proteínas Proto-Oncogênicas p21(ras)
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Linfócitos T CD8-Positivos
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Proteínas rac de Ligação ao GTP
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Complexo de Endopeptidases do Proteassoma
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Epitopos
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Antígenos de Neoplasias
/
Neoplasias
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Elife
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Alemanha