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.
Highlights
Activating CD8+ T cells to recurrent tumor-specific mutations is one of a number of cuttingedge strategies to treat cancer
Epitope production is the first step of the antigen processing and presentation (APP) pathway, which accounts for the epitope translocating into the endoplasmic reticulum (ER) lumen through mediation by transporters associated with antigen processing (TAPs), binding to the peptide loading complex, trimming by exopeptidases, binding to the Human Leukocyte Antigen class I (HLA-I) complex, and transport to the cell surface for recognition by cytotoxic T lymphocytes (CTLs) [2]
Antigens represented by spliced peptides in HLA-I immunopeptidomes tend to be preferentially long, hydrophobic and basic, thereby suggesting that the chemical and physical characteristics of antigens can impinge upon spliced peptide generation and presentation [12, 24]
Summary
Activating CD8+ T cells to recurrent tumor-specific mutations is one of a number of cuttingedge strategies to treat cancer. It can be achieved by immunotherapy approaches such as adoptive T cell therapy (ATT), peptide vaccination and dendritic cell (DC) vaccination. The most active proteasome isoform is a large (26S) protease consisting of a 20S proteasome core coupled to one or two 19S regulatory complexes. Human cells can express different isoforms of catalytic subunits, which are incorporated in distinct proteasome isoforms. Tumors express various intermediate-type proteasome isoforms, in which standard- and immuno-subunits are assembled in one proteasome complex [4, 5]. Tumors express various intermediate-type proteasome isoforms, in which standard- and immuno-subunits are assembled in one proteasome complex [4, 5]. 20S proteasome is functional alone in cells or coupled to other regulatory subunits such as PA28 αβ [3, 6, 7]
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