Journal
FRONTIERS IN IMMUNOLOGY
Volume 10, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2019.02572
Keywords
proteasome; peptide splicing; adoptive T cell therapy targets; antigen presentation; cancer epitopes; KRAS; tumor immunology
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Funding
- NIH [R21Al134127]
- Cancer Research UK King's Health Partners Center at King's College London (Development Fund 2018)
- KCL-Monash Collaborative Award 2018
- MPI-BPC collaboration agreement 2018
- BIH grant [CRG1-TP1]
- NC3Rs through a David Sainsbury Fellowship at Imperial College London [NC/K001949/1]
- International Max Planck Research School (IMPRS) for Genome Science
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Targeting CD8(+) T cells to recurrent tumor-specific mutations can profoundly contribute to cancer treatment. Some of these mutations are potential tumor antigens although they can be displayed by non-spliced epitopes only in a few patients, because of the low affinity of the mutated non-spliced peptides for the predominant HLA class I alleles. Here, we describe a pipeline that uses the large sequence variety of proteasome-generated spliced peptides and identifies spliced epitope candidates, which carry the mutations and bind the predominant HLA-I alleles with high affinity. They could be used in adoptive T cell therapy and other anti-cancer immunotherapies for large cohorts of cancer patients. As a proof of principle, the application of this pipeline led to the identification of a KRAS G12V mutation-carrying spliced epitope candidate, which is produced by proteasomes, transported by TAPs and efficiently presented by the most prevalent HLA class I molecules, HLA-A*02:01 complexes.
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