An efficient T-cell epitope discovery strategy using in silico prediction and the iTopia assay platform

Arthur Fridman, Adam C. Finnefrock, Daniela Peruzzi, Irene Pak, Nicola La Monica, Ansuman Bagchi, Danilo R. Casimiro, Gennaro Ciliberto, Luigi Aurisicchio

Research output: Contribution to journalArticlepeer-review

Abstract

Functional T-cell epitope discovery is a key process for the development of novel immunotherapies, particularly for cancer immunology. In silico epitope prediction is a common strategy to try to achieve this objective. However, this approach suffers from a significant rate of false-negative results and epitope ranking lists that often are not validated by practical experience. A high-throughput platform for the identification and prioritization of potential T-cell epitopes is the iTopiaTM Epitope Discovery SystemTM, which allows measuring binding and stability of selected peptides to MHC Class I molecules. So far, the value of iTopia combined with in silico epitope prediction has not been investigated systematically. In this study, we have developed a novel in silico selection strategy based on three criteria: (1) predicted binding to one out of five common MHC Class I alleles; (2) uniqueness to the antigen of interest; and (3) increased likelihood of natural processing. We predicted in silico and characterized by iTopia 225 candidate T-cell epitopes and fixed-anchor analogs from three human tumor-associated antigens: CEA, HE R2 and TERT. HLA-A2-restricted fragments were further screened for their ability to induce cell-mediated responses in HLA-A2 transgenic mice. The iTopia binding assay was only marginally informative while the stability assay proved to be a valuable experimental screening method complementary to in silico prediction. Thirteen novel T-cell epitopes and analogs were characterized and additional potential epitopes identified, providing the basis for novel anticancer immunotherapies. In conclusion, we show that combination of in silico prediction and an iTopia-based assay may be an accurate and efficient method for MHC Class I epitope discovery among tumor-associated antigens.

Original languageEnglish
Pages (from-to)1258-1270
Number of pages13
JournalOncoImmunology
Volume1
Issue number8
DOIs
Publication statusPublished - 2012

Keywords

  • Cancer vaccine
  • CEA
  • Epitope prediction
  • HER2/neu
  • TERT

ASJC Scopus subject areas

  • Immunology and Allergy
  • Oncology
  • Immunology

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