Identification of an MSI-H tumor-specific cytotoxic T cell epitope generated by the (-1) frame of U79260(FTO)

J Biomed Biotechnol. 2010;2010:841451. doi: 10.1155/2010/841451. Epub 2010 Mar 18.

Abstract

Microsatellite instability (MSI-H) induced by defects of the DNA mismatch repair system results in insertion or deletion of single nucleotides at short repetitive DNA sequences. About 15% of sporadic and approximately 90% of hereditary nonpolyposis colorectal cancers display MSI-H. When affecting coding regions, MSI-H results in frameshift mutations and expression of corresponding frameshift peptides (FSPs). Functional tumor promoting relevance has been demonstrated for a growing number of genes frequently hit by MSI-H. Contrary, immune reactions against FSPs are involved in the immune surveillance of MSI-H cancers. Here, we provide conclusive data that the (-1) frame of U79260(FTO) encodes an HLA-A0201-restricted cytotoxic T cell epitope (FSP11; TLSPGWSAV). T cells specific for FSP11 efficiently recognized HLA-A0201((pos)) tumor cells harboring the mutated reading frame. Considering the exceptionally high mutation rate of U79260(FTO) in MSI-H colorectal carcinoma (81.8%), this recommends that FSP11 be a component of future vaccines.

MeSH terms

  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • Cell Death
  • Cell Line, Tumor
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / metabolism
  • Epitopes, T-Lymphocyte / genetics*
  • Epitopes, T-Lymphocyte / immunology
  • Flow Cytometry
  • Frameshift Mutation
  • HCT116 Cells
  • HLA-A Antigens / genetics
  • HLA-A Antigens / immunology
  • HLA-A2 Antigen
  • Humans
  • Immunoenzyme Techniques
  • Leukocytes, Mononuclear / immunology
  • Microsatellite Instability*
  • Peptides / genetics
  • Peptides / immunology*
  • Proteins / genetics
  • Proteins / immunology*
  • T-Lymphocytes, Cytotoxic / immunology*

Substances

  • Epitopes, T-Lymphocyte
  • HLA-A Antigens
  • HLA-A*02:01 antigen
  • HLA-A2 Antigen
  • Peptides
  • Proteins
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • FTO protein, human