1. An in silico—in vitro Pipeline Identifying an HLA-A*02:01+ KRAS G12V+ Spliced Epitope Candidate for a Broad Tumor-Immune Response in Cancer Patients
- Author
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Michele Mishto, Artem Mansurkhodzhaev, Ge Ying, Aruna Bitra, Robert A. Cordfunke, Sarah Henze, Debdas Paul, John Sidney, Henning Urlaub, Jacques Neefjes, Alessandro Sette, Dirk M. Zajonc, and Juliane Liepe
- Subjects
proteasome ,peptide splicing ,adoptive T cell therapy targets ,antigen presentation ,cancer epitopes ,KRAS ,Immunologic diseases. Allergy ,RC581-607 - Abstract
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.
- Published
- 2019
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