Identification of C-met oncogene as a broadly expressed tumor-associated antigen recognized by cytotoxic T-lymphocytes

Clin Cancer Res. 2004 Jun 1;10(11):3658-66. doi: 10.1158/1078-0432.CCR-03-0640.

Abstract

Purpose: C-Met proto-oncogene is a receptor tyrosine kinase that mediates the oncogenic activities of the hepatocyte growth factor. Using a DNA chip analysis of tumor samples from patients with renal cell carcinoma and sequencing of peptides bound to the HLA-A*0201 molecules on tumor cells a peptide derived from the c-Met protein was identified recently.

Experimental design: We used this novel HLA-A*0201 peptide for the induction of specific CTLs to analyze the presentation of this epitope by malignant cells.

Results: The induced CTL efficiently lysed target cells pulsed with the cognate peptide, as well as HLA-A*0201-matched tumor cell lines in an antigen-specific and HLA-restricted manner. Furthermore, the induced c-Met-specific CTLs recognized autologous dendritic cells (DCs) pulsed with the peptide or transfected with whole-tumor mRNA purified from c-Met-expressing cell lines. We next induced c-Met-specific CTLs using peripheral blood mononuclear cells and DC from an HLA-A*0201-positive patient with plasma cell leukemia to determine the recognition of primary autologous malignant cells. These CTLs lysed malignant plasma cells while sparing nonmalignant B- and T-lymphocytes, monocytes, and DCs.

Conclusion: Our results demonstrate that c-Met oncogene is a novel tumor rejection antigen recognized by CTL and expressed on a broad variety of epithelial and hematopoietic malignant cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens / chemistry
  • Antigens, Neoplasm / chemistry*
  • B-Lymphocytes / metabolism
  • Blotting, Western
  • Carcinoma, Renal Cell / genetics*
  • Cell Line, Tumor
  • Dendritic Cells / cytology
  • Electrophoresis, Polyacrylamide Gel
  • Electroporation
  • Enzyme-Linked Immunosorbent Assay
  • Epitopes / chemistry
  • HLA-A Antigens / biosynthesis
  • HLA-A Antigens / genetics
  • HLA-A2 Antigen
  • Humans
  • Interferon-gamma / metabolism
  • Kidney Neoplasms / genetics*
  • Leukocytes, Mononuclear / metabolism
  • Monocytes / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Peptides / chemistry
  • Proto-Oncogene Proteins c-met / biosynthesis*
  • Proto-Oncogene Proteins c-met / genetics*
  • RNA / metabolism
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes / metabolism
  • T-Lymphocytes, Cytotoxic / metabolism*
  • Time Factors

Substances

  • Antigens
  • Antigens, Neoplasm
  • Epitopes
  • HLA-A Antigens
  • HLA-A*02:01 antigen
  • HLA-A2 Antigen
  • Peptides
  • RNA, Messenger
  • RNA
  • Interferon-gamma
  • Proto-Oncogene Proteins c-met