Abstract
Identification of tumor antigens that induce cytotoxic T lymphocytes (CTLs) is crucial for cancer-vaccine development. Despite their predictive ability, current algorithmic approaches and human leukocyte antigen (HLA)-peptidomic analysis allow limited selectivity. Here, we optimized a method to rapidly screen and identify highly immunogenic epitopes that trigger CTL responses. We used a combined application of this method involving immune-specific signature analysis and HLA-associated peptidomics using samples from six patients with triple-negative breast cancer (TNBC) in order to select immunogenic HLA epitopes for in vitro testing. Additionally, we applied high-throughput imaging at the single-cell level in order to confirm the immunoreactivity of the selected peptides. The results indicated that this method enabled identification of promising CTL peptides capable of inducing antitumor immunity. This platform combining high-resolution computational analysis, HLA-peptidomics, and high-throughput immunogenicity testing allowed rapid and robust identification of highly immunogenic epitopes and represents a powerful technique for cancer-vaccine development.
Highlights
Identification of tumor antigens that induce cytotoxic T lymphocytes (CTLs) is crucial for cancervaccine development
Proteomics approaches associated with mass spectrometry (MS)[25] and LC-MS/MS, were used for human leukocyte antigen (HLA)-peptidomic analysis to directly facilitate the discovery of numerous natural peptides in complex with specific HLA molecules expressed on cell surfaces[26,27]
Large amounts of tumor-infiltrating lymphocyte (TIL) correlate with improved tumor survival[30]; we preselected TIL-resident triple-negative breast cancer (TNBC) tissues for histologic analysis to identify potentially promising cancer epitopes (Fig. 2a and Supplementary Fig. S1) and scored TIL density by measuring the proportion of the stromal area infiltrated by lymphocytes, as previously described[31]
Summary
Identification of tumor antigens that induce cytotoxic T lymphocytes (CTLs) is crucial for cancervaccine development Despite their predictive ability, current algorithmic approaches and human leukocyte antigen (HLA)-peptidomic analysis allow limited selectivity. We used a combined application of this method involving immune-specific signature analysis and HLA-associated peptidomics using samples from six patients with triple-negative breast cancer (TNBC) in order to select immunogenic HLA epitopes for in vitro testing. The results indicated that this method enabled identification of promising CTL peptides capable of inducing antitumor immunity This platform combining high-resolution computational analysis, HLApeptidomics, and high-throughput immunogenicity testing allowed rapid and robust identification of highly immunogenic epitopes and represents a powerful technique for cancer-vaccine development. We established a rapid and robust screening system combining immune-signature investigation, HLA-peptidomic analysis, and high-throughput immunogenicity testing to evaluate antigen-specific CTL responses (Fig. 1)
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