Frameshift Peptide-Derived T-cell Epitopes: A Source of Novel Tumor-Specific Antigens

Int J Cancer. 2001 Jul 1;93(1):6-11. doi: 10.1002/ijc.1298.

Abstract

Microsatellite instability (MSI) caused by defective DNA mismatch repair (MMR) is a hallmark of hereditary nonpolyposis colorectal cancers (HNPCC) but also occurs in about 15% of sporadic tumors. If instability affects microsatellites in coding regions, translational frameshifts lead to truncated proteins often marked by unique frameshift peptide sequences at their C-terminus. Since MSI tumors show enhanced lymphocytic infiltration and our previous analysis identified numerous coding mono- and dinucleotide repeat-bearing candidate genes as targets of genetic instability, we examined the role of frameshift peptides in triggering cellular immune responses. Using peptide pulsed autologous CD40-activated B cells, we have generated cytotoxic T lymphocytes (CTL) that specifically recognize HLA-A2.1-restricted peptides derived from frameshift sequences. Among 16 frameshift peptides predicted from mutations in 8 different genes, 3 peptides conferred specific lysis of target cells exogenously loaded with cognate peptide. One peptide derived from a (-1) frameshift mutation in the TGFbetaIIR gene gave rise to a CTL bulk culture capable of lysing the MSI colorectal cancer cell line HCT116 carrying this frameshift mutation. Given the huge number of human coding microsatellites and assuming only a fraction being mutated and encoding immunologically relevant peptides in MSI tumors, frameshift protein sequences represent a novel subclass of tumor-specific antigens. It is tempting to speculate that a frameshift peptide-directed vaccination approach not only could offer new treatment modalities for existing MSI tumors but also might benefit asymptomatic at-risk individuals in HNPCC families by a prophylactic vaccination strategy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antigens, CD / immunology
  • B-Lymphocytes / immunology*
  • Base Pair Mismatch
  • CD40 Antigens / immunology*
  • CD40 Ligand / immunology
  • Colonic Neoplasms / immunology*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics
  • DNA Repair
  • Frameshift Mutation
  • HLA-A2 Antigen / chemistry
  • HLA-A2 Antigen / genetics*
  • Humans
  • Microsatellite Repeats / genetics
  • Peptide Fragments / chemistry
  • Peptide Fragments / immunology*
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / immunology
  • T-Lymphocytes, Cytotoxic / immunology*
  • Tumor Cells, Cultured

Substances

  • Antigens, CD
  • CD40 Antigens
  • HLA-A2 Antigen
  • Peptide Fragments
  • Receptors, Transforming Growth Factor beta
  • CD40 Ligand
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II