and cell-based analyses reveal strong divergence between prediction and observation of T-cell-recognized tumor antigen T-cell epitopes.

Journal: The Journal of biological chemistry
PMID: 28536262

Abstract

Tumor exomes provide comprehensive information on mutated, overexpressed genes and aberrant splicing, which can be exploited for personalized cancer immunotherapy. Of particular interest are mutated tumor antigen T-cell epitopes, because neoepitope-specific T cells often are tumoricidal. However, identifying tumor-specific T-cell epitopes is a major challenge. A widely used strategy relies on initial prediction of human leukocyte antigen-binding peptides by algorithms, but the predictive power of this approach is unclear. Here, we used the human tumor antigen NY-ESO-1 (ESO) and the human leukocyte antigen variant HLA-A*0201 (A2) as a model and predicted the 41 highest-affinity, A2-binding 8-11-mer peptides and assessed their binding, kinetic complex stability, and immunogenicity in A2-transgenic mice and on peripheral blood mononuclear cells from ESO-vaccinated melanoma patients. We found that 19 of the peptides strongly bound to A2, 10 of which formed stable A2-peptide complexes and induced CD8 T cells in A2-transgenic mice. However, only 5 of the peptides induced cognate T cells in humans; these peptides exhibited strong binding and complex stability and contained multiple large hydrophobic and aromatic amino acids. These results were not predicted by algorithms and provide new clues to improving T-cell epitope identification. In conclusion, our findings indicate that only a small fraction of -predicted A2-binding ESO peptides are immunogenic in humans, namely those that have high peptide-binding strength and complex stability. This observation highlights the need for improving predictions of peptide immunogenicity.

Authors

  • Julien Schmidt
    Ludwig Institute for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland.
  • Philippe Guillaume
    Ludwig Institute for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland.
  • Danijel Dojcinovic
    Ludwig Institute for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland.
  • Julia Karbach
    Krankenhaus Nordwest, 60488 Frankfurt, Germany.
  • George Coukos
    Ludwig Institute for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland; Department of Oncology, University Hospital of Lausanne, 1011 Lausanne, Switzerland.
  • Immanuel Luescher
    Ludwig Institute for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland. Electronic address: immanuel.luescher@unil.ch.

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