Dendritic cell-based immunotherapy for colon cancer using an HLA-A*0201-restricted cytotoxic T-lymphocyte epitope from tumor-associated antigen 90K

Cell Mol Immunol. 2013 May;10(3):275-82. doi: 10.1038/cmi.2012.74. Epub 2013 Mar 25.

Abstract

Tumor-associated antigen 90K is implicated in cell-cell and cell-extracellular matrix adhesion through its interaction with galectin-3 and integrin-β1 and is highly expressed in malignant tissues, making it a novel target for the development of new immunotherapies. We investigated a potential immunotherapy treatment for colon cancer using 90K-specific cytotoxic T lymphocytes induced by autologous dendritic cells and pulsed with 90K peptides. We selected three peptides (90K351, 90K5 and 90K523) that bind to HLA-A*0201 molecules on the basis of their binding affinity, as determined by a peptide-T2 binding assay. Dendritic cells pulsed with 90K peptides resulted in the efficient generation of mature dendritic cells and exhibited enhanced T-cell stimulation and polarization of naive T cells toward Th1. Dendritic cells pulsed with 90K peptides generated potent cytotoxic T-lymphocytes that lysed T2 cells loaded with each 90K peptide, and 90K(+)/HLA-A2(+) colon cancer cell lines, including HCT116 and SW480, in a dose-dependent and HLA-A*0201-restricted manner. No killing was observed in 90K(+)/HLA-A2(-) DLD1 or 90K(-)/HLA-A2(-) K562 cells. Therefore, we believe that cytotoxic T-lymphocytes stimulated by 90K peptide-pulsed dendritic cells naturally recognize the 90K peptide presented by colon cancer cells in the context of HLA-A2, and kill 90K-positive tumor cells. Dendritic cells pulsed with 90K peptides led to the induction of granzyme B and perforin positive CD8(+) T cells against HCT116 and SW480 cells, but not DLD1 cells. In conclusion, 90K-specific cytotoxic T lymphocytes, generated by stimulating T cells with 90K peptide-pulsed dendritic cells, could be useful effector cells for the immunotherapy treatment of colon cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antigens, Neoplasm / chemistry
  • Antigens, Neoplasm / immunology*
  • Biomarkers, Tumor / chemistry
  • Biomarkers, Tumor / immunology*
  • Carrier Proteins / chemistry
  • Carrier Proteins / immunology*
  • Cell Line, Tumor
  • Colonic Neoplasms / immunology
  • Colonic Neoplasms / therapy*
  • Dendritic Cells / immunology*
  • Epitopes / chemistry
  • Epitopes / immunology*
  • Glycoproteins / chemistry
  • Glycoproteins / immunology*
  • HLA-A2 Antigen / immunology*
  • Humans
  • Immunotherapy*
  • Molecular Sequence Data
  • Peptides / chemistry
  • Protein Binding / immunology
  • T-Lymphocytes, Cytotoxic / immunology*

Substances

  • Antigens, Neoplasm
  • Biomarkers, Tumor
  • Carrier Proteins
  • Epitopes
  • Glycoproteins
  • HLA-A*02:01 antigen
  • HLA-A2 Antigen
  • LGALS3BP protein, human
  • Peptides